Friedlaender condensation of 5-aminopyrazole-4-carbaldehydes with reactive α-methylene ketones: Synthesis of pyrazolo[3,4-b]pyridines

Article abstract of DOI:10.1002/jhet.5570420710

A series of 1,3,6-trisubstituted and 1,3,5,6-tetrasubstituted pyrazolo[3,4-b]pyridines 5 has been synthesized by Friedlaender condensation of 5-aminopyrazole-4-carbaldehydes 3 with α-methylene ketones such as acetone (4a) or acetophenones 4b-f with potass

Full text of DOI:10.1002/jhet.5570420710

Nov-Dec 2005
1311
Friedländer Condensation of 5-Aminopyrazole-4-carbaldehydes with
Reactive α-Methylene Ketones:
Synthesis of Pyrazolo[3,4-b]pyridines
*
Madhukar N. Jachak , Appasaheb B. Avhale, Chanda D. Tantak, Raghunath B. Toche,
Post Graduate Department of Chemistry, K. R. T. Arts, B. H. Commerce and A. M. Science College, Gangapur
Road, Nashik-422 002, India
Claudia Reidlinger and Wolfgang Stadlbauer
Institute of Chemistry, Karl-Franzens University of Graz,
Heinrichstrasse 28, A-8010 Graz, Austria/Europe
Received April 13, 2005
A series of 1,3,6-trisubstituted and 1,3,5,6-tetrasubstituted pyrazolo[3,4-b]pyridines 5 has been synthe-
sized by Friedländer condensation of 5-aminopyrazole-4-carbaldehydes 3 with α-methylene ketones such
as acetone (4a) or acetophenones 4b-f with potassium hydroxide as basic catalyst. Condensation of
5-aminopyrazole-4-carbaldehydes 3 and unsymmetric dialkylketones 6 yielded mixtures of isomeric pyra-
zolo[3,4-b]pyridine derivatives 7 and 8. Condensation of 5-aminopyrazole-4-carbaldehydes 3 with CH-
acidic acylacetonitriles 9 and acylacetates 11 with piperidine as basic catalyst yielded pyrazolo[3,4-b]pyri-
dine-5-carbonitriles 10 and pyrazolo[3,4-b]pyridine-5-carboxylates 12; with diethyl malonate 13 as CH-
acidic component, pyrazolo[3,4-b]pyridin-6-ones 14 were obtained.
J. Heterocyclic Chem., 42, 1311 (2005).
Pyrazolo[3,4-b]pyridines as aza-analogues of indazoles
Friedländer condensation, 5-aminopyrazole-4-carbalde-
hydes 3, were synthesized by cyclocondensation of p-sub-
stituted aroylacetonitriles, a class of compounds which
was studied recently by us for other cyclization reactions
[12]. p-Substituted aroylacetonitriles cyclize as 1,3-dicar-
bonyl synthons with arylhydrazines already on heating
without catalysts according to known methods [13] and
furnished in good to excellent yields 5-aminopyrazoles 1,
which afforded on Vilsmeier-Haack formylation with
excess dimethylformamide and phosphoryl chloride 4-
formyl-pyrazolyl-dimethylimidoformamides 2. Thermal
analysis of formamides 2 by differential scanning
calorimetry (DSC) revealed that they are thermally stable
compounds which showed thermal decomposition only
above 350 °C. Hydrolysis of formamides 2 with refluxing
ethanolic sodium hydroxide yielded the required 5-
aminopyrazole-4-carbaldehydes 3 in good yield.
[1] are attractive targets in organic synthesis due to their
significant biological activities, such as hypoglycemic [2],
psychotropic [3], cytotoxic [4] or antiviral [5] activity, and
in coronary [6] or neurodegenerative diseases [7].
o-Aminoaldehydes are the key intermediates for the syn-
thesis of various biologically active heterocycles e.g. [8,9]
using the Friedländer reaction with ketones in a 4+2
cyclocondensation [10], which prompted us to investigate
the reaction pathway of 5-aminopyrazole-4-carbaldehydes
with α-methylene ketones to new 1,3,6-trisubstituted and
1,3,5,6-tetrasubstituted pyrazolo[3,4-b]pyridines, espe-
cially to 1,3,6-triarylpyrazolo[3,4-b]pyridines. A literature
survey shows a few reports on the synthesis of pyra-
zolo[3,4-b]pyridines using the Friedländer condensation
[11], however with substitution patterns different to ours.
The required starting materials for the intended
Scheme 1

1312
M. N. Jachak, A. B. Avhale, C. D. Tantak, R. B. Toche, C. Reidlinger and W. Stadlbauer
Vol. 42
The Friedländer condensation of o-aminoaldehydes such
as 5-aminopyrazole-4-carbaldehydes 3 with ketones is
described to take place either with strong bases or acids as
catalysts; in special cases the ring closure can be observed
without a catalyst at higher temperatures (e.g. under
microwave irradiation) [10]. We obtained the best results
when a mixture of the appropriate 5-aminopyrazole-4-car-
baldehyde 3 and the corresponding ketone 4 or 6 were
brought to reaction in refluxing ethanolic potassium hydrox-
ide solution. With acetone (4a) or acetophenones 4b-f, this
reaction sequence afforded 6-alkyl-3-aryl and 3,6-diaryl-1-
phenylpyrazolo[3,4-b]pyridines 5a-l in good yields.
because 7a shows two methyl singlets at 2.42 and 2.64
ppm, together with the singlet of 4-H at 7.98 ppm, whereas
8a shows the ethyl signal at 1.44 and 2.98 ppm, together
with two doublets at 7.14 and 8.21 ppm assigned to the
ortho coupled protons 4-H and 5-H of the pyridine ring.
All other signals of aromatic protons are nearly identical.
Mass spectral analysis of 7a and 8a showed in both cases
37
the same mass of 333 (M) and 335 m/z (M+2, Cl iso-
tope), however with other fragmentation patterns: the
dimethyl derivative 7a showed as the main fragmentation
297 m/z without chloro pattern, which indicates a cleavage
of HCl, whereas 8a shows as the first fragmentation 318
When instead of the symmetric acetone (4a) or
monoalkylketones (4b-f) unsymmetric dialkyl ketones
such as 2-butanone (6a) or 4-phenyl-2-butanone (6b) were
used as condensation partner, a mixture of the two
expected isomers 7 and 8 was obtained in a 2:1 ratio; the 5-
substituted isomer 7 was formed by attack of the carbalde-
m/z, a cleavage of CH , together with the fragment 297
m/z as observed at 7a. Similarly, the structures of bromo
derivatives 7b and 8b could be assigned. Compound 7b
3
shows the methyl singlet at 2.66 and the benzyl-CH sin-
2
glet at 4.20 ppm; the 4-H signal appeared at 8.07 ppm. The
isomer 8b shows two CH -multiplets at 3.22-3.27 and
2
hyde moiety at the ethyl- or benzyl-CH group of the
3.32-3.38 ppm, and H-4 and H-5 doublets at 7.11 and 8.23
ppm. The mass spectra of the two isomer bromo deriva-
tives 7c and 8c revealed again the identical masses, 377
(M) and 379 m/z (M+2, Br isotope).
As mentioned above, the Friedländer condensation can
2
ketone 6, whereas condensation on the alpha-methyl group
of 6 formed the 5-unsubstituted isomer 8. The mixture of
the isomers 7 and 8 was separated by column chromatogra-
phy using toluene/hexane as the eluent. Structural assign-
81
1
ment of 7a and 8a could easily be performed by H nmr,
be catalyzed by various agents [10]. When we extended
Scheme 2

Nov-Dec 2005
Friedländer Condensation of 5-Aminopyrazole-4-carbaldehydes
1313
our synthetic investigations to CH-acidic compounds such
as benzoylacetonitriles 9, β-ketoesters 11 or diethyl mal-
onate 13 as keto-component, we found that already piperi-
dine as base was sufficiently strong to catalyze the conden-
sation reaction, which allowed also the preparation of sen-
sitive substituents such as ester groups without decomposi-
tion. This method provided a versatile method for the syn-
thesis of various substituted pyrazolo[3,4-b]pyridines and
pyrazolo[3,4-b]pyridones with reactive groups in position
5, ready for further reactions. The cyclocondensation of 5-
aminopyrazole-4-carbaldehydes 3 with benzoylacetoni-
triles 9 yielded in ethanolic piperidine pyrazolo[3,4-
b]pyridine-5-carbonitriles 10 and β-ketoesters 11 gave
pyrazolo[3,4-b]pyridine-5-carboxylates 12, both structures
easily confirmed by nitrile and ester signals. Diethyl mal-
onate (13) afforded under these conditions 5-carbethoxy-
pyrazolo[3,4-b]pyridin-6-ones 14. The mass spectra and
nmr data confirmed the structures of 14, although the ester
carbonyl stretch in the IR could not be observed either in
KBr disks or nujol suspension, probably because of hydro-
gen bonding in the solid state.
The thermal behavior of two pyrazolo[3,4-b]pyridine-5-
carbonitriles 10 were investigated by differential scanning
calorimetry (DSC) and show above 350 °C reaction peaks,
a reaction temperature too high for synthetic use.
EXPERIMENTAL
Melting points were determined on a Gallenkamp Melting
Point Apparatus, Mod. MFB-595 in open capillary tubes.
Scheme 3

1314
M. N. Jachak, A. B. Avhale, C. D. Tantak, R. B. Toche, C. Reidlinger and W. Stadlbauer
Vol. 42
Calorimetric data were obtained on a Rheometric Scientific
DSC-Plus instrument with the differential scanning calorimetry
software Orchestrator V6.2.2. The differential scanning
calorimetry (DSC) plots were recorded between 25 - 500 °C, with
a heating rate of 2-10 °C/min, and 1.5-3 mg compound in sealed
decomposition at 374.3 °C onset, 394.8 °C maximum, ∆H = –139
-1
1
J/g; ir: 1650 s, 1600 m cm ; H nmr: δ 3.05 (s, CH ), 3.16 (s,
3
CH ), 7.26-7.44 (m, 3 ArH), 7.60-7.87 (m, 6 ArH), 8.63 (s,
3
N=CH), 9.67 (s, CH=O).
Anal. Calcd. for C H BrN O: C, 57.44; H, 4.31; N, 14.10.
19 17
4
1
aluminium crucibles (11 bar). The H nmr spectra were recorded
Found: C, 57.40; H, 4.06; N, 13.92.
on a Varian XL-300 spectrometer (300 MHz), a Bruker AMX
360 instrument (360 MHz) or a Bruker Avance DRX 500 instru-
ment (500 MHz). The C nmr-spectra were recorded on a
N'-[4-Formyl-3-(4-methylphenyl)-1-phenyl-1H-pyrazol-5-yl]-
N,N-dimethylimidoformamide (2c).
13
Bruker AM 360 instrument (90 MHz). Chemical shifts are
reported in ppm from internal tetramethylsilane standard and are
given in δ-units. The solvent for NMR spectra was deuteriochlo-
This compound was obtained from 3-(4-methylphenyl)-1-
phenyl-1H-pyrazol-5-amine (1c) (24.9 g, 0.1 mol) using the proce-
dure described for 2a; the yield was 24.0 g (72%), colorless prisms,
1
-1 1
roform unless otherwise stated. Evaluation of H nmr spectra was
mp 127-128 °C (ethanol); ir: 1655 s, 1620 m cm ; H nmr: δ 2.41
performed using the software Mestrec 4. Infrared spectra were
taken on a Shimadzu IR-408, a Shimadzu FTIR, or on a Galaxy
Series FTIR 7000 instrument in potassium bromide pellets unless
otherwise stated. Elemental analyses were performed on a Hosli
CH-Analyser or on a Fisons elemental analyzer Mod. EA 1108,
and are within 0.4 of the theoretical percentages. Mass spectra
were taken on a HP 1100 LC/MSD mass spectral instrument
(positive or negative APCI: 50-200 eV, nitrogen). All reactions
were monitored by thin layer chromatography, carried out on 0.2
mm silica gel 60 F-254 (Merck) plates using uv light (254 and
366 nm) for detection. Column chromatography was carried out
on silica gel (SD Fine Chemicals, 60-80 mesh). Common
reagent-grade chemicals are either commercially available and
were used without further purification or prepared by standard
literature procedures.
(s, Ar-CH ), 3.04 (s, N-CH ), 3.15 (s, N-CH ), 7.26-7.42 (m, 5
3 3 3
PhH), 7.57-7.89 (m, 4 ArH), 8.71 (s, N=CH), 9.70 (s, CH=O).
Anal. Calcd. for C H N O: C, 72.27; H, 6.06; N, 16.86.
20 20
4
Found: C, 72.16; H, 6.19; N, 16.94.
5-Amino-3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-carbalde-
hyde (3a).
A solution of pyrazolylimidoformamide 2a (35.2 g, 0.1 mol) in
ethanol (275 mL) and aqueous sodium hydroxide solution (27.5
mL, 40%) was heated under reflux for 2 hours. It was then poured
into water (800 mL) and the precipitated solid was filtered by
suction, washed with water and dried. The yield was 20.5 g
(69%), pale yellow prisms, mp 137-138 °C (ethanol); ir: 3450 m,
-1 1
3345 m, 1642 s cm ; H nmr: δ 6.00 (s, NH , exchangeable with
2
2
D O), 7.37-7.68 (m, 9 ArH), 9.85 (s, CH=O).
Anal. Calcd. for C H ClN O: C, 64.54; H, 4.06; N, 14.11.
Found: C, 64.23; H, 3.96; N, 14.24.
16 12
3
3-(4-Substituted aryl)-1-phenyl-1H-pyrazol-5-amines 1a-c.
These compounds were synthesized from p-chloro-, p-bromo-
or p-methyl-benzoylacetonitrile [12] and phenylhydrazine in
excellent yields by refluxing in ethanol for 4-6 h according to ref.
[13].
5-Amino-3-(4-bromophenyl)-1-phenyl-1H-pyrazole-4-carbalde-
hyde (3b).
This compound was obtained from pyrazolylimidoformamide
2b (39.7 g, 0.1 mol) using the procedure described for 3a; the yield
was 23.9 g (70%), pale yellow prisms, mp 142-143 °C (ethanol); ir:
N'-[3-(4-Chlorophenyl)-4-formyl-1-phenyl-1H-pyrazol-5-yl]-
N,N-dimethylimidoformamide (2a).
-1 1
3350 m, 3450 m, 1645 s cm ; H nmr: δ 6.01 (s, NH , exchange-
2
To a solution of 3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-5-
amine (1a) (26.9 g, 0.1 mol) in dimethylformamide (37 mL, 0.5
mol), phosphoryl chloride (46 mL, 0.3 mol) was added in small
portions at 10-15 °C with stirring. Then the reaction mixture was
stirred at 65-70 °C for 3.5 hours and poured into ice/water (900
mL). The precipitated product was filtered by suction, and
washed with water. The yield was 27.5 g (78%) colorless prisms,
mp 133-134 °C (ethanol); calorimetric data for the thermolysis:
mp at 136.1 °C onset, 137.7 °C maximum, ∆H = 107 J/g, decom-
position at 346.5 °C onset, 347.9 °C maximum, ∆H = –61 J/g,
decomposition at 448.7 °C onset, 448.9 °C maximum, ∆H = –451
able with D O), 7.44-7.60 (m, 9 ArH), 9.83 (s, CH=O).
2
Anal. Calcd. for C H BrN O: C, 56.16; H, 3.53; N, 12.28.
16 12
3
Found: C, 56.05; H, 3.63; N, 12.08.
5-Amino-3-(4-methylphenyl)-1-phenyl-1H-pyrazole-4-carbalde-
hyde (3c).
This compound was obtained from pyrazolylimidoformamide
2c (33.2 g, 0.1 mol) using the procedure described for 3a; the
yield was 18.8 g (68%), pale yellow prisms, mp 130-131 °C
-1
1
(ethanol); ir: 3350 m, 3455 m, 1645 s cm ; H nmr: δ 2.41 (s,
CH ), 5.98 (s, NH , exchangeable with D O), 7.28-7.61 (m, 9
3
2
2
-1
1
J/g; ir: 1655 s, 1615 m cm ; H nmr: δ 2.86 (s, CH ), 2.97 (s,
ArH), 9.85 (s, CH=O).
3
CH ), 7.32-7.62 (m, 5 PhH), 7.63-7.65 (m, 4 ArH), 8.48 (s,
Anal. Calcd. for C H N O: C, 73.63; H, 5.45; N, 15.15.
3
17 15
3
N=CH), 9.52 (s, CH=O).
Found: C, 73.36; H, 5.68; N, 15.32.
Anal. Calcd. for C H ClN O: C, 64.68; H, 4.86; N, 15.88.
Found: C, 64.80; H, 4.76; N, 15.98.
19 17
4
3-(4-Chlorophenyl)-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyri-
dine (5a).
N'-[3-(4-Bromophenyl)-4-formyl-1-phenyl-1H-pyrazol-5-yl]-
N,N-dimethylimidoformamide (2b).
A mixture of pyrazolecarbaldehyde 3a (0.59 g, 2 mmol), ace-
tone (4a) (0.12 g, 2 mmol) and ethanolic potassium hydroxide
solution (10 mL, 2%) was heated under reflux for one hour. The
mixture was then cooled to room temperature and the obtained
solid was collected by suction filtration and washed with ethanol.
The yield was 0.39 g (61%), colorless prisms, mp 140-141°
This compound was obtained from 3-(4-bromophenyl)-1-
phenyl-1H-pyrazol-5-amine (1b) (3.14 g, 0.1 mol) using the pro-
cedure described for 2a; the yield was 30.1 g (76%), colorless
prisms, mp 138-139 °C (ethanol); calorimetric data for the ther-
molysis: mp at 142.3 °C onset, 144.2 °C maximum, ∆H = 85 J/g,
-1 1
(ethyl acetate); ir: 2350 w, 1600 m cm ; H nmr: δ 2.75 (s, CH ),
3

Nov-Dec 2005
Friedländer Condensation of 5-Aminopyrazole-4-carbaldehydes
1315
7.13 (d, J = 8.4 Hz, 5-H), 7.28-7.55 (m, 5 PhH), 7.96 (d, J = 8.4
Hz, 2 ArH), 8.20 (d, J = 8.4 Hz, 4-H), 8.36 (d, J = 8.4 Hz, 2 ArH).
8.7 Hz, 2 ArH), 7.31-7.57 (m, 5 ArH), 7.67 (d, J = 8.4 Hz, 5-H),
7.97 (d, J = 8.7 Hz, 2 ArH), 8.15 (d, J = 8.7 Hz, 2 ArH), 8.31 (d,
J = 8.4 Hz, 4-H) 8.46 (d, J = 8.7 Hz, 2 ArH).
Anal. Calcd. for C H ClN : C, 71.36; H, 4.41; N, 13.14.
19 14
3
Anal. Calcd. for C H ClN O: C, 72.90; H, 4.40; N, 10.20.
Found: C, 71.56; H, 4.77; N, 13.29.
25 18
3
Found: C, 73.11; H, 4.43; N, 10.12.
3-(4-Chlorophenyl)-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine
(5b).
3-(4-Bromophenyl)-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]-
pyridine (5g).
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and acetophenone (4b) (0.24 g, 2 mmol) using
the method and work-up as described for 5a; the yield was 0.52 g
(68%) pale yellow prisms, mp 164-165 °C (ethyl acetate); ir:
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and acetone (4a) (0.12 g, 2 mmol) using the
method described for 5a; the yield was 0.44 g (60%), colorless
-1
-1 1
prisms, mp 144-145 °C (ethyl acetate); ir: 2335 w, 1596 m cm ;
2345 w, 1600 m cm ; H nmr: δ 7.33-7.56 (m, 8 ArH), 7.75 (d, J
1
H nmr: δ 2.74 (s, CH ), 7.12 (d, J = 8.4 Hz, 5-H), 7.28-7.66 (m,
= 8.4 Hz, 5-H), 8.00 (d, J = 8.4 Hz, 2 ArH), 8.19 (d, J = 7.8 Hz, 2
ArH), 8.38 (d, J = 8.4 Hz, 4-H), 8.50 (d, J = 7.8 Hz, 2 ArH).
3
5 PhH), 7.89 (d, J = 8.4 Hz, 2 ArH), 8.19 (d, J = 8.4 Hz, 4-H),
8.36 (d, J = 7.5 Hz, 2 ArH).
Anal. Calcd. for C H ClN : C, 75.49; H, 4.22; N, 11.00.
24 16
3
Anal. Calcd. for C H BrN : C, 62.65; H, 3.87; N, 11.54.
Found: C, 75.62; H, 4.06; N, 11.23.
19 14
3
Found: C, 62.82; H, 3.65; N, 11.74.
3,6-Bis(4-chlorophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine
(5c).
3-(4-Bromophenyl)-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine
(5h).
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and 4-chloroacetophenone (4c) (0.31 g, 2
mmol) using the method described for 5a; the yield was 0.63 g
(75%), pale yellow prisms, mp 196-198 °C (ethyl acetate); ir:
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and acetophenone (4b) (0.24 g, 2 mmol) using
the method described for 5a; the yield was 0.57 g (66%), pale
yellow prisms, mp 168-170 °C (ethyl acetate); ir: 2339 w, 1594
-1
1
2339 w, 1591 m, cm ; H nmr: δ 7.34-7.59 (m, 7 ArH), 7.70 (d,
J = 8.4 Hz, 5-H), 8.01 (d, J = 8.4 Hz, 2 ArH), 8.10 (d, J = 8.7 Hz,
2 ArH), 8.37 (d, J = 8.4 Hz, 4-H), 8.40 (d, J = 8.7 Hz, 2 ArH).
-1
1
m, cm ; H nmr: δ 7.33-7.59 (m, 6 ArH), 7.65 (d, J = 7.5 Hz, 2
ArH), 7.75 (d, J = 8.4 Hz, 5-H), 7.94 (d, J = 7.8 Hz, 2 ArH), 8.19
(d, J = 8.4 Hz, 2 ArH), 8.36 (d, J = 8.4 Hz, 4-H), 8.47 (d, J = 7.5
Hz, 2 ArH).
Anal. Calcd. for C H Cl N : C, 69.24; H, 3.63; N, 10.09.
24 15
2 3
Found: C, 69.54; H, 3.40; N, 9.92.
Anal. Calcd. for C
H BrN : C, 67.62; H, 3.78; N 9.86.
24 16 3
6-(4-Bromophenyl)-3-(4-chlorophenyl)-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine (5d).
Found: C, 67.86; H, 3.50; N, 9.70.
3-(4-Bromophenyl)-6-(4-chlorophenyl)-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine (5i).
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and 4-bromoacetophenone (4d) (0.40 g, 2
mmol) using the method described for 5a; the yield was 0.66 g
(72%), pale yellow prisms, mp 199-200 °C (ethyl acetate); ir:
This compound was obtained from pyrazolecarbaldehyde
3b (0.68 g, 2 mmol) and 4-chloroacetophenone (4c) (0.31 g, 2
mmol) using the method described for 5a; the yield was 0.68 g
(73%), pale yellow prisms, mp 199-201 °C (ethyl acetate); ir:
-1 1
2335 w, 1595 m cm ; H nmr: δ 7.34-7.66 (m, 7 ArH), 7.68 (d, J
= 8.7 Hz, 5-H), 8.00 (d, J = 8.1 Hz, 2 ArH), 8.02 (d, J = 8.4 Hz, 2
ArH), 8.35 (d, J = 8.7 Hz, 4-H), 8.42 (d, J = 8.4 Hz, 2 ArH).
-1
1
2335 w, 1591 m cm ; H nmr: δ 7.30-7.64 (m, 7 ArH), 7.71
(d, J = 8.4 Hz, 5-H), 7.90 (d, J = 7.2 Hz, 2 ArH), 8.08 (d, J =
7.5 Hz, 2 ArH), 8.35 (d, J = 8.4 Hz, 4-H), 8.42 (d, J = 8.1 Hz,
2 ArH).
Anal. Calcd. for C H Br N : C, 62.56; H, 3.28; N, 9.12.
24 15 Cl
3
Found: C, 62.31; H, 3.14; N 9.06.
Anal. Calcd. for C H BrClN : C, 62.56; H, 3.28; N 9.12.
Found: C, 62.62; H, 3.38; N, 9.20.
3-(4-Chlorophenyl)-6-(4-methylphenyl)-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine (5e).
24 15
3
3,6-Bis(4-bromophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine
(5j).
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and 4-methylacetophenone (4e) (0.27 g, 2 mmol)
using the method described for 5a; the yield was 0.56 g (71%),
colorless prisms, mp 192-194 °C (ethyl acetate); ir: 2338 w, 1600
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and 4-bromoacetophenone (4d) (0.40 g, 2
mmol) using the method described for 5a; the yield 0.71 g (70%),
pale yellow prisms, mp 204-205 °C (ethyl acetate); ir: 1593 m,
-1 1
m cm ; H nmr: δ 2.45 (s, CH ), 7.31-7.64 (m, 7 ArH), 7.71 (d, J
3
= 8.4 Hz, 5-H), 7.92 (d, J = 8.7 Hz, 2 ArH), 8.05 (d, J = 6.6 Hz, 2
ArH), 8.32 (d, J = 8.4 Hz, 4-H), 8.47 (d, J = 7.5 Hz, 2 ArH).
Anal. Calcd. for C H ClN : C, 75.85; H, 4.58; N, 10.61.
-1
1
2336 w cm ; H nmr: δ 7.34-7.68 (m, 7 ArH), 7.69 (d, J = 8.7
Hz, 5-H), 7.91 (d, J = 8.4 Hz, 2 ArH), 8.02 (d, J = 8.4 Hz, 2 ArH),
8.36 (d, J = 8.7 Hz, 4-H), 8.42 (d, J = 7.5 Hz, 2 ArH).
25 18
3
Found: C, 75.45; H, 4.71; N, 10.45.
Anal. Calcd. for C H Br N : C, 57.06; H, 2.99; N 8.32.
Found: C, 56.68; H, 2.99; N, 8.30.
24 15
2 3
3-(4-Chlorophenyl)-6-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine (5f).
3-(4-Bromophenyl)-6-(4-methylphenyl)-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine (5k).
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and 4-methoxyacetophenone (4f) (0.30 g, 2
mmol) using the method described for 5a; the yield was 0.62 g
(75%), colorless prisms, mp 209-210 °C (ethyl acetate); ir: 2336
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and 4-methylacetophenone (4e) (0.27 g, 2
mmol) using the method described for 5a; the yield was 0.50 g
-1
1
w, 1747 m, 1595 m cm ; H nmr: δ 3.89 (s, OCH ), 7.02 (d, J =
3

1316
M. N. Jachak, A. B. Avhale, C. D. Tantak, R. B. Toche, C. Reidlinger and W. Stadlbauer
Vol. 42
(70%) colorless prisms, mp 195-196 °C (ethyl acetate); ir: 2339
was 0.39 g (51%), colorless prisms, mp 168-170 °C (ethyl
-1
1
-1 1
w, 1595 m cm ; H nmr: δ 2.45 (s, CH ) 7.32-7.65 (m, 7 ArH),
acetate); ir: 2284 w, 1596 m, 1554 m cm ; H nmr: δ 2.45 (s,
3
7.72 (d, J = 8.4 Hz, 5-H), 7.93 (d, J = 8.7 Hz, 2 ArH), 8.06 (d, J =
8.4 Hz, 2 ArH), 8.34 (d, J = 8.4 Hz, 4-H), 8.47 (d, J = 8.7 Hz, 2
ArH).
CH ), 2.68 (s, CH ), 7.28-7.62 (m, 5 PhH), 7.89 (d, J = 8.1 Hz, 2
3
3
ArH), 8.01 (s, 4-H), 8.38 (d, J = 8.1 Hz, 2 ArH); ms: m/z (%) 379
(100, M+2), 377 (87, M), 334 (9), 333 (42).
Anal. Calcd. for C H BrN : C, 63.50; H, 4.26; N 11.11.
Anal. Calcd. for C
H BrN : C, 68.19; H, 4.12; N 9.54.
20 16
3
25 18 3
Found: C, 63.27; H, 4.05; N, 10.92.
Found: C, 68.24; H, 4.16; N, 9.60.
5-Benzyl-3-(4-bromophenyl)-6-methyl-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine (7d).
3-(4-Bromophenyl)-6-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine (5l).
This compound was obtained from the pyrazolecarbaldehyde
3b (0.68 g, 2 mmol) and 4-phenylbutan-2-one (6b) (0.30 g, 2
mmol); the yield was 0.48 g (53%), colorless prisms, mp 183-184
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and 4-methoxyacetophenone (4f) (0.30 g, 2
mmol) using the method described for 5a; the yield was 0.67 g
(73%) colorless prisms, mp 212-214 °C (ethyl acetate); ir: 2335
-1
1
°C (ethyl acetate); ir: 2284 w, 1596 m, 1555 m cm ; H nmr: δ
-1
1
2.66 (s, CH ), 4.20 (s, CH ), 7.16-7.66 (m, 10 PhH), 7.91 (d, J =
w, 1745 m, 1596 m cm ; H nmr: δ 3.90 (s, OCH ), 7.03-7.51
3
2
3
8.1 Hz, 2 ArH), 8.06 (s, 4-H) , 8.44 (d, J = 8.1 Hz, 2 ArH).
Anal. Calcd. for C BrN : C, 68.73; H, 4.44; N 9.25.
(m, 7ArH), 7.65 (d, J = 8.7 Hz, 5-H), 7.93 (d, J = 8.7 Hz, 2 ArH),
8.13 (d, J = 9.0 Hz, 2 ArH), 8.33 (d, J = 8.7 Hz, 4-H), 8.46 (d, J =
8.1 Hz, 2 ArH).
H
26 20
3
Found: C, 68.56; H, 4.52; N, 9.30.
Anal. Calcd. for C H BrN O: C, 65.80; H, 3.98; N, 9.21.
Found: C, 65.52; H, 4.21; N, 9.46.
25 18
3
3-(4-Chlorophenyl)-6-ethyl-1-phenyl-1H-pyrazolo[3,4-b]-
pyridine (8a).
General Procedure for the Preparation of 3-(4-Halophenyl)-1-
phenyl-1H-pyrazolo[3,4-b]pyridines 7 and 8.
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and 2-butanone (6a) (0.14 g, 2 mmol); the yield
was 0.14 g (21%) colorless prisms, mp 136-138 °C (ethyl
A mixture of the appropriate pyrazolecarbaldehyde 3 (2 mmol),
the corresponding ketone 4 (2 mmol) and ethanolic potassium
hydroxide solution (10 mL, 2%) was heated under reflux for one
hour. A colorless solid precipitated and was filtered by suction. It
-1 1
acetate); ir: 2283 w, 1595 m, 1556 m cm ; H nmr: δ 1.44 (t, J =
7.2 Hz, CH ), 2.98 (q, J = 7.2 Hz, CH ), 7.14 (d, J = 8.4 Hz, 5-H),
3
2
7.27-7.53 (m, 5 ArH), 7.96 (d, J = 8.7 Hz, 2 ArH), 8.21 (d, J = 8.4
Hz, 4-H), 8.42 (d, J = 8.7, 1 ArH); ms: m/z (%) 335 (31, M+2),
333 (100, M), 318 (74, M–15), 317 (35), 297 (20, M–36), 282
(14), 181 (27).
contained two compounds according to tlc analysis (R values:
f
0.95 and 0.73 in toluene). This mixture was dissolved in acetone
and separated by column chromatography (18 x 300 mm, eluent
toluene/hexane 5:100, eluation volume for 7: 400-420 mL, for 8:
240-260 mL); detection by tlc analysis (254 nm).
Anal. Calcd. for C H ClN : C, 71.96; H, 4.83; N, 12.59.
20 16
3
Found: C, 71.84; H, 4.81; N, 12.78.
3-(4-Chlorophenyl)-1-phenyl-6-(2-phenylethyl)-1H-pyrazolo-
[3,4-b]pyridine (8b).
3-(4-Chlorophenyl)-5,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]-
pyridine (7a).
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and 4-phenylbutan-2-one (6b) (0.30 g, 2 mmol);
the yield was 0.22 g (24%), colorless prisms, mp 148-150 °C
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and 2-butanone (6a) (0.14 g, 2 mmol); the yield
was 0.35 g (52%), colorless prisms, mp 161-162 °C (ethyl
-1 1
(ethyl acetate); ir: 2285 w, 1593 m, 1553 m cm ; H nmr: δ 3.22-
-1
1
acetate); ir: 2283 w, 1595 m, 1556 m cm ; H nmr: δ 2.42 (s,
3.27 (m, CH ), 3.32-3.38 (m, CH ), 7.11 (d, J = 8.4 Hz, 5-H),
2
2
CH ), 2.64 (s, CH ), 7.22-7.51 (m, 5 PhH), 7.92 (d, J = 8.4 Hz, 2
3
3
7.24- 7.57 (m, 10 PhH), 8.00 (d, J = 8.7 Hz, 2 ArH), 8.23 (d, J =
8.4 Hz, 4-H), 8.42 (d, J = 8.4 Hz, 2 ArH).
ArH), 7.98 (s, 4-H), 8.35 (d, J = 8.4 Hz, 2 ArH); ms: m/z (%) 335
(40, M+2), 333 (100, M), 297 (17, M–36), 221 (20), 196 (30),
194 (5), 181 (24).
Anal. Calcd. for C H ClN : C, 76.18; H, 4.92; N, 10.25.
26 20
3
Found: C, 76.42; H, 5.20; N, 10.45.
Anal. Calcd. for C H ClN : C, 71.96; H, 4.83; N, 12.59.
20 16
3
3-(4-Bromophenyl)-6-ethyl-1-phenyl-1H-pyrazolo[3,4-b]-
pyridine (8c).
Found: C, 71.80; H, 4.78; N, 12.76.
5-Benzyl-3-(4-chlorophenyl)-6-methyl-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine (7b).
This compound was obtained from pyrazolecarbaldehyde 3b
(0.69 g, 2 mmol) and 2-butanone (6a) (0.14 g, 2 mmol); the yield
was 0.15 g (20%), colorless prisms, mp 142-143 °C (ethyl
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and 4-phenylbutan-2-one (6b) (0.30 g, 2 mmol);
the yield was 0.50 g (55%), colorless prisms, mp 174-175 °C
-1 1
acetate); ir: 2283 w, 1595 m, 1554 m cm ; H nmr: δ 1.44 (t, J =
7.8 Hz, CH ), 3.01 (q, J = 7.8 Hz, CH ), 7.14 (d, J = 8.1 Hz, 5-H),
3
2
-1 1
(ethyl acetate); ir: 2282 w, 1593 m, 1552 m cm ; H nmr: δ 2.66
7.17-7.63 (m, 5 ArH), 7.90 (d, J = 8.1 Hz, 2 ArH), 8.21 (d, J = 8.1
Hz, 4-H), 8.42 (d, J = 8.1 Hz, 2 ArH); ms: m/z (%) 379 (100,
M+2), 377 (85, M), 335 (5), 333 (21).
(s, CH ), 4.20 (s, CH ), 7.16-7.59 (m, 10 PhH), 7.97 (d, J = 8.4
3
2
Hz, 2 ArH), 8.07 (s, 4-H), 8.44 (d, J = 8.4 Hz, 2 ArH).
Anal. Calcd. for C H ClN : C, 76.18; H, 4.92; N, 10.25.
Anal. Calcd. for C H BrN : C, 63.50; H, 4.26; N 11.11.
26 20
3
20 16
3
Found: C, 76.38; H, 5.14; N, 10.48.
Found: C, 63.74; H, 4.21; N, 10.95.
3-(4-Bromophenyl)-5,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]-
pyridine (7c).
3-(4-Bromophenyl)-1-phenyl-6-(2-phenylethyl)-1H-pyrazolo-
[3,4-b]pyridine (8d).
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and 4-phenylbutan-2-one (6b) (0.30 g, 2 mmol);
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and 2-butanone (6a) (0.14 g, 2 mmol); the yield

Nov-Dec 2005
Friedländer Condensation of 5-Aminopyrazole-4-carbaldehydes
1317
the yield was 0.20 g (22%), colorless prisms, mp 154-155 °C
3-(4-Bromophenyl)-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile (10e).
-1 1
(ethyl acetate); ir: 2287 w, 1594 m, 1556 m cm ; H nmr: δ 3.22-
3.27 (m, CH ), 3.32-3.38 (m, CH ), 7.11 (d, J = 8.4 Hz, 5-H),
2
2
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and 3-oxo-3-phenylpropanenitrile (9a) (0.29 g,
2 mmol) using the method described for 10a; the yield was 0.63 g
(70%) colorless prisms, mp 268-269 °C (dimethylformamide); ir:
7.20-7.66 (m, 10 PhH), 7.94 (d, J = 8.4 Hz, 2 ArH), 8.23 (d, J =
8.4 Hz, 4-H), 8.42 (d, J = 8.4 Hz, 2 ArH).
Anal. Calcd. for C
H BrN : C, 68.73; H, 4.44; N 9.25.
26 20 3
Found: C, 68.65; H, 4.58; N, 9.22.
-1
1
2221 s, 1596 s, 1543 m cm ; H nmr (CF COOD): δ 7.81-7.98
3
(m, 5 PhH, 2 ArH), 8.00 (d, J = 7.2 Hz, 2 ArH), 8.02-8.13 (m, 4
ArH), 9.61 (s, 4-H).
3-(4-Chlorophenyl)-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile (10a).
Anal. Calcd. for C H BrN : C, 66.53; H, 3.35; N, 12.41.
25 15
4
A solution of pyrazolecarbaldehyde 3a (0.59 g, 2 mmol) and 3-
oxo-3-phenylpropanenitrile (9a) (0.29 g, 2 mmol) in ethanol (10
mL) and piperidine (0.5 mL) was heated under reflux for 30 min.
The solid obtained on cooling was filtered by suction and washed
with cold ethanol (5 mL). The yield was 0.59 g (72%), colorless
prisms, mp 256-257 °C (dimethylformamide); ir: 2250 s, 1594 s,
Found: C, 66.60; H, 3.48; N, 12.68.
3-(4-Bromophenyl)-6-(4-chlorophenyl)-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine-5-carbonitrile (10f).
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and 3-(4-chlorophenyl)-3-oxopropanenitrile
(9b) (0.36 g, 2 mmol) using the method described for 10a; the
yield was 0.67 g (69%), colorless prisms, mp 289-290 °C
-1
1
1550 m cm ; H nmr (CF COOD): δ 7.99-8.12 (m, 5 PhH, 4
3
ArH), 8.19 (d, J = 7.3 Hz, 2 ArH), 8.32 (d, J = 7.4 Hz, 2 ArH),
9.72 (s, 4-H).
-1
1
(dimethylformamide); ir: 2229 s, 1595 s, 1541 m cm ; H nmr
Anal. Calcd. for C H ClN : C, 73.80; H, 3.72; N, 13.77.
25 15
4
(CF COOD): δ 7.85 (d, J = 7.4 Hz, 2 ArH), 7.90-7.94 (m, 4
3
Found: C, 73.62; H, 3.42; N, 13.62.
ArH), 7.98-8.11(m, 5 PhH, 2 ArH), 9.53 (s, 4-H).
Anal. Calcd. for C H Br N : C, 61.18; H, 2.99; N, 11.53.
Found: C, 61.20; H, 3.17; N, 11.74.
3,6-Bis(4-chlorophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-
5-carbonitrile (10b).
25 14 Cl
4
3,6-Bis(4-bromophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-
5-carbonitrile (10g).
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and 3-(4-chlorophenyl)-3-oxopropanenitrile (9b)
(0.36 g, 2 mmol) using the method described for 10a; the yield was
0.65 g (73%), colorless prisms, mp 282-283 °C (dimethylfor-
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and 3-(4-bromophenyl)-3-oxopropanenitrile
(9c) (0.45 g, 2 mmol) using the method described for 10a; the
yield was 0.74 g (70%) colorless prisms, mp 300-301 °C
-1 1
mamide); ir: 2250 s, 1596 s, 1545 m cm ; H nmr (CF COOD): δ
3
7.89 (d, J = 7.3 Hz, 2 ArH), 7.95-7.98 (m, 5 PhH), 8.04-8.11 (m, 4
ArH), 8.22 (d, J = 7.2 Hz, 2 ArH), 9.56 (s, 4-H).
-1
1
(dimethylformamide); ir: 2225 s, 1593 s, 1541m cm ; H nmr
Anal. Calcd. for C H Cl N : C, 68.04; H, 3.20; N 12.70.
25 14
2 4
(CF COOD): δ 7.94-8.05 (5 PhH, 6 ArH), 8.21 (d, J = 7.2 Hz, 2
3
Found: C, 68.81; H, 3.13; N, 12.95.
ArH), 9.54 (s, 4-H).
Anal. Calcd. For C H Br N : C, 56.63; H, 2.66; N, 10.57.
Found: C, 56.87; H, 2.55; N, 10.56.
6-(4-Bromophenyl)-3-(4-chlorophenyl)-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine-5-carbonitrile (10c).
25 14
2 4
3-(4-Bromophenyl)-6-(4-methylphenyl)-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine-5-carbonitrile (10h).
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and 3-(4-bromophenyl)-3-oxopropanenitrile
(9c) (0.45 g, 2 mmol) using the method described for 10a; the
yield was 0.69 g (71%) colorless prisms, mp 290-291 °C
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and 3-(4-methylphenyl)-3-oxopropanenitrile (9d)
(0.32 g, 2 mmol) using the method described for 10a; the yield was
0.65 g (70%), colorless prisms, mp 292-293 °C (dimethylfor-
mamide); calorimetric data for the thermolysis: mp at 296.7 °C
onset, 298.2 °C maximum, ∆H = 90 J/g, decomposition at 372.4
°C onset, 378.4 °C maximum, ∆H = –55 J/g, mp at 418.7 °C onset,
419.2 °C maximum, ∆H = 3 J/g, decomposition at 420.5 °C onset,
424.6 °C maximum, ∆H = –228 J/g; ir: 3550-3270 s, 3064 w, 2225
-1
1
(dimethylformamide); ir: 2250 s, 1593 s, 1545 m cm ; H nmr
(CF COOD): δ 7.99-8.11 (m, 5 PhH, 4 ArH), 8.24-8.28 (m, 4
3
ArH), 9.60 (s, 4-H).
Anal. Calcd. for C H BrClN : C, 61.18; H, 2.99; N, 11.53.
25 14
4
Found: C, 61.25; H, 3.10; N, 11.74.
3-(4-Chlorophenyl)-6-(4-methylphenyl)-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine-5-carbonitrile (10d).
-1
1
m, 1605 sh, 1594s, 1542 m cm ; H nmr (CF COOH): δ 2.86 (s,
3
This compound was obtained from pyrazolecarbaldehyde 3a
(0.59 g, 2 mmol) and 3-(4-methylphenyl)-3-oxopropanenitrile
(9d) (0.32 g, 2 mmol) using the method described for 10a; the
yield was 0.59 g (70%), mp 285-286 °C (dimethylformamide);
calorimetric data for the thermolysis: mp at 286.3 °C onset, 287.5
°C maximum, ∆H = 101 J/g, mp at 412.6 °C onset, 413.9 °C
maximum, ∆H = 114 J/g, decomposition at 420.1 °C onset, 424.3
°C maximum, ∆H = –140 J/g; ir: 3590-3270 m, 3062 w, 2225 m,
CH ), 7.85 (d, J = 7.4 Hz, 2 ArH), 8.04-8.11 (m, 5 PhH, 2 ArH),
3
8.22 (d, J = 7.2 Hz, 4 ArH), 9.74 (s, 4-H).
Anal. Calcd. for C H BrN : C, 67.07; H, 3.68; N, 12.04.
26 17
4
Found: C, 67.95; H, 3.87; N, 12.28.
Ethyl 3-(4-Chlorophenyl)-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]-
pyridine-5-carboxylate (12a).
A solution of pyrazolecarbaldehyde 3a (0.60 g, 2 mmol) and
ethyl 3-oxobutanoate (11a) (0.26 g, 2 mmol) in ethanol (10 mL)
and piperidine (0.5 mL) was heated under reflux for 4 hours. The
solid obtained on cooling was filtered by suction and washed with
cold ethanol (5 mL). The yield was 0.31 g (61%), colorless prisms,
-1 1
1595 s, 1543 w cm ; H nmr (CF COOH): δ 2.85 (s, CH ), 7.83
3
3
(d, J = 7.4 Hz, 2 ArH), 8.01-8.10 (m, 5 PhH, 4 ArH), 8.29 (d, J =
7.2 Hz, 2 ArH), 9.73 (s, 4-H).
Anal. Calcd. for C H ClN : C, 74.19; H, 4.07; N, 13.31.
26 17
4
-1 1
Found: C, 74.07; H, 3.86; N, 13.18.
mp 119-120 °C (ethyl acetate); ir: 1730 s, 1592 s, 1556 m cm ; H

1318
M. N. Jachak, A. B. Avhale, C. D. Tantak, R. B. Toche, C. Reidlinger and W. Stadlbauer
Vol. 42
nmr: δ 1.44 (t, J = 7.2 Hz, CH ), 3.01 (s, CH ), 4.41 (q, J = 7.2 Hz,
Ethyl 3-(4-Bromophenyl)-6-oxo-1-phenyl-6,7-dihydro-1H-pyra-
zolo[3,4-b]pyridine-5-carboxylate (14b).
3
3
CH ), 7.33-7.57 (m, 5 PhH), 7.97 (d, J = 8.4 Hz, 2 ArH), 8.36 (d, J
2
= 8.4 Hz, 2 ArH), 8.90 (s, 4-H).
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and diethyl malonate (13) (0.32 g, 2 mmol) using
the method described for 14a; the yield was 0.49 g (62%) colorless
prisms, mp 142-143 °C (ethyl acetate); ir: 3500-3200 m, b, 1681 s,
Anal. Calcd. for C H ClN O : C, 82.61; H, 5.67; N, 13.14.
22 18
3 2
Found: C, 82.82; H, 5.56; N, 13.28.
Ethyl 3-(4-Chlorophenyl)-1,6-diphenyl-1H-pyrazolo[3,4-b]pyri-
dine-5-carboxylate (12b).
-1 1
1617m, 1596m, 1561 w cm ; H nmr: δ 1.49 (t, J = 7.2 Hz, CH ),
3
4.49 (q, J = 7.2 Hz, CH ), 7.29-7.65 (m, 5 PhH), 7.84 (d, J = 8.7 Hz,
2
This compound was obtained from pyrazolecarbaldehyde 3a
(0.60 g, 2 mmol) and ethyl 3-oxo-3-phenylpropanoate (11b) (0.38
g, 2 mmol) using the method described for 12a; the yield was 0.52
g (57%), colorless prisms, mp 173-174 °C (ethyl acetate); ir: 1720
2 ArH), 8.26 (d, J = 8.1 Hz, 2 ArH), 8.83 (s, 4-H), 12.05 (s, NH,
exchangeable by deuterium oxide); ms: m/z (%) 439 (33, M+2), 437
(36, M), 379 (88), 377 (100, M–60), 335 ( 31), 333 (79).
Anal. Calcd. for C H BrN O : C, 57.55; H, 3.68; N, 9.59.
21 16
3 3
-1 1
s, 1596 s, 1550 m cm ; H nmr: δ 1.04 (t, J = 7.2 Hz, CH ), 4.15
3
Found: C, 57.62; H, 3.60; N, 9.65.
(q, J = 7.2 Hz, CH ), 7.29-7.67 (m, 10 PhH), 8.01 (d, J = 8.4 Hz, 2
2
ArH), 8.40 (d, J = 7.8 Hz, 2 ArH), 8.81 (s, 4-H).
Acknowledgment.
Anal. Calcd. for C H ClN O : C, 71.44; H, 4.44; N 9.26.
27 20
3 2
The authors thank Nashik District Maratha Vidya Prasarak
Samaj, Nashik and Principal, K. R. T. Arts, B. H. Commerce and
A. M. Science College, Nashik, India, for academic leave and
facilities. R. B. T. and C. D. T. thank the University Grants
Commission for financial support and Dr. D. D. Dhavale for
valuable discussions.
Found: C, 71.63; H, 4.40; N, 9.35.
Ethyl 3-(4-Bromophenyl)-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]-
pyridine-5-carboxylate (12c).
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and ethyl 3-oxobutanoate (11a) (0.26 g, 2
mmol) using the method described for 12a; the yield was 0.53 g
(60%) colorless prisms, mp 128-129 °C (ethyl acetate); ir: 1706
REFERENCES AND NOTES
-1 1
s, 1593 s, 1552 m cm ; H nmr: δ 1.43 (t, J = 7.2 Hz, CH ), 2.99
3
(s, CH ), 4.40 (q, J = 7.2 Hz, CH ), 7.30-7.64 (m, 5 PhH) 7.89 (d,
3
2
[1] W. Stadlbauer, in Houben-Weyl - Science of Synthesis, 12, 227
(2002) (R. Neier ed.); Georg-Thieme, Stuttgart, New York 2002.
[2] G. M. Anton-Fos, R. Garcia-Domenech,, F. Perez-Gimenez, J.
E. Peris-Ribera, F. J. Garcia-March and M. T. Salabert-Salvador,
Arzneimittel-Forschung, 44, 821 (1994).
[3] F. A. Feurer, J. Luithle, S.-N. Wirtz, G. Koenig, J.-P. Stasch,
E. Stahl, R. Schreiber, F. Wunder and D. Lang, (Bayer Healthcare AG,
Germany), PCT Int. Appl., WO 2004009589 (2004); Chem. Abstr., 140,
146157 (2004); J. Ehlert, P. Ragan, A. Chen, W. R. Roeske and H. I.
Yamamura, Europ. J. Pharmacol., 78, 249 (1982); J. B. Patel, J. B.
Malick, A. I. Salama and M. E. Goldberg, Pharmacol., Biochem. and
Behavior, 23, 675 (1985); R. Young, R. A. Glennon, W. L. Dewey,
Psychopharm. (Berlin), 93, 494 (1987).
J = 8.4 Hz, 2 ArH), 8.35 (d, J = 7.8 Hz, 2 ArH), 8.87 (s, 4-H).
Anal. Calcd. for C H BrN O : C, 60.56; H, 4.16; N; 9.63.
22 18
3 2
Found: C, 60.56; H, 4.35; N, 9.72.
Ethyl 3-(4-Bromophenyl)-1,6-diphenyl-1H-pyrazolo[3,4-b]pyri-
dine-5-carboxylate (12d).
This compound was obtained from pyrazolecarbaldehyde 3b
(0.68 g, 2 mmol) and ethyl 3-oxo-3-phenylpropanoate (11b) (0.38
g, 2 mmol) using the method described for 12a; the yield was 0.55
g (55%), colorless prisms, mp 180-181 °C (ethyl acetate); ir: 1712
-1 1
s, 1595 s, 1548 m cm ; H nmr: δ 1.02 (t, J = 7.2 Hz, CH ), 4.14
3
(q, J = 7.2 Hz, CH ), 7.28-7.69 (m, 10 PhH), 7.94 (d, J = 8.7 Hz, 2
[4] Y. S. Sanghvi, S. B. Larson, R. C. Willis, R. K. Robins and G.
R. Revankar, J. Med. Chem., 32, 945 (1989).
2
ArH), 8.38 (d, J = 8.1 Hz, 2 ArH), 8.79 (s, 4-H).
[5] S. Ludwig, O. Planz, H.-H. Sedlacek and S. Pleschka
(Medinnova Ges.m.b.H., Germany), PCT Int. Appl., WO 2004085682
(2004); Chem. Abstr., 141, 307497 (2004); Ger. Offen., DE 10138912
(2003); Chem. Abstr., 138, 198569 (2003).
[6] H. Bischoff and J.-P. Stasch, (Bayer AG, Germany), PCT Int.
Appl., WO 2003015770 (2003); Chem. Abstr., 138, 180718 (2003).
[7] I. A. Aiet, A. Resink and F. Schweighoffer (Exonhit
Therapeutics S. A., France), U.S. Pat., 2004219552 (2004); Chem. Abstr.,
141, 388737 (2004); PCT Int. Appl., WO 2003016563 (2003); Chem.
Abstr., 138, 203092 (2003).
Anal. Calcd. for C H BrN O : C, 65.07; H, 4.04; N, 8.43.
Found: C, 65.10; H, 4.13; N, 8.52.
27 20
3 2
Ethyl 3-(4-Chlorophenyl)-6-oxo-1-phenyl-6,7-dihydro-1H-pyra-
zolo[3,4-b]pyridine-5-carboxylate (14a).
A solution of pyrazolecarbaldehyde 3a (0.60 g, 2 mmol) and
diethyl malonate (13) (0.32 g, 2 mmol) in ethanol (10 mL) and
piperidine (0.5 mL) was heated under reflux for 1 hour. The solid
obtained on cooling was collected by suction filtration and washed
with cold ethanol (5 mL). The yield was 0.61 g (78%) colorless
prisms, mp 133-134 °C (ethyl acetate); ir: 3450 w, 1674 s, 1670 sh,
[8] E. Hawes and D. K. J. Gorecki, J. Heterocyclic Chem., 9, 703
(1972); 11, 151 (1974).
[9] K. Reddy, K. Mogilaiah and B. Sreenivasulu, J. Ind. Chem.
Soc., 63, 443, 984 (1986).
-1
-
1619 w, 1595 m cm ; ir (nujol): 2950-2850 s, 1673 m, 1660 m cm
1
1
; H nmr: δ 1.47 (t, J = 7.2 Hz, CH ), 4.49 (q, J = 7.2 Hz, CH ),
7.31 (t, J = 7.1 Hz, 1 ArH), 7.47-7.53 (m, 4 ArH), 7.90 (d, J = 8.4
Hz, 2 ArH), 8.27 (d, J = 8.4 Hz, 2 ArH), 8.82 (s, 4-H), 12.06 (s,
NH, exchangeable by deuterium oxide); C nmr (DMSO-d ): δ
14.5 (Me), 61.9 (CH ), 109.0, 109.4, 121.5, 126.9, 129.2, 129.6,
3
2
[10] C.-C. Cheng and S.-Y. Yan, in Organic Reactions, 28, 37
(1982); J. Wiley, New York 1982; B. P. Mundy and M. G. Ellerd, Name
Reactions and Reagents in Organic Synthesis, p. 86; J. Wiley and
Sons, New York, Chichester, Brisbane, Toront, Singapore 1988; A.
Hassner and C. Stumer, Organic Synthesis Based On Named and
Unnamed Reactions (Tetrahedron Organic Chemistry Series), 11, 132
(1994) (J. E. Baldwin, P. D. Magnus, eds), Elsevier Science, Oxford,
New York, Tokyo 1994; A. Diaz-Ortiz, A. de la Hoz and F. Langa,
Green Chem., 2, 165 (2000); G. Karthikeyan and P.T. Perumal, J.
Heterocyclic Chem., 41, 1039 (2004).
13
6
2
129.7, 130.8, 134.3, 136.5, 138.8, 144.4, 150.9 (14 ArC), 163.2
(ester-C=O), 166.8 (amide-C=O); ms: m/z (%) 395 (24, M+2), 393
(100, M), 323 (10), 321 (38).
Anal. Calcd. for C H ClN O : C, 64.05; H, 4.10; N, 10.67.
21 16
3 3
Found: C, 64.11; H, 4.34; N, 10.86.

Nov-Dec 2005
Friedländer Condensation of 5-Aminopyrazole-4-carbaldehydes
1319
[11] G. Sabitha, R. Srividya, B. Archana and J. S. Yadav, Synth.
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Tomasik, ARKIVOC, 2 (2001); A. Al-Enezi, B. Al-Saleh and M. H.
Elnagdi, J. Chem. Res., Synop., 4 (1997).
[12] M. N. Jachak, C. D. Tantak, R. B. Toche and N. S. Badgujar,
Monatsh. Chem., 135, 1529 (2004).
[13] N. L. Nam, I. I. Grandberg, V. I. Sorokin and K. A.
Timiryazev, Chem. Heterocycl. Comp. (New York), 39, 937 (2003); P.
Wang, Z. Xie, Z. Hong, J. Tang, O. Wong, C.-S. Lee, N. Wong and S. Lee,
J. Mat. Chem., 13, 1894 (2003); A. Simay, K. Takacs, K. Horvath, and P.
Dvortsak, Acta Chim. Acad. Sci. Hung., 105, 127 (1980); K. C. Joshi, V.
N. Pathak and U. Garg, J. Heterocycl. Chem., 16, 1141 (1979).