Cyclocondensation reactions of 5-aminopyrazoles, pyruvic acids and aldehydes. Multicomponent approaches to pyrazolopyridines and related products

Article abstract of DOI:10.1016/j.tet.2006.11.048

The reactions of 3-substituted 5-aminopyrazoles with arylidenepyruvic acids and their synthetic precursors, pyruvic acid and aromatic aldehydes, were studied. Several different reaction pathways for these cyclocondensation reactions were established depen

Full text of DOI:10.1016/j.tet.2006.11.048

Tetrahedron 63 (2007) 1229–1242
Cyclocondensation reactions of 5-aminopyrazoles, pyruvic
acids and aldehydes. Multicomponent approaches to
pyrazolopyridines and related products
a
a
Valentin A. Chebanov,a,b, Yana I. Sakhno, Sergey M. Desenko,
*
Vitaliy N. Chernenko,a Vladimir I. Musatov,a Svetlana V. Shishkina,a
Oleg V. Shishkina and C. Oliver Kappeb
aDepartment of Heterocyclic Compounds Chemistry, State Scientific Institution ‘Institute for Single Crystals’
of National Academy of Sciences of Ukraine, Lenin Avenue 60, 61001 Kharkiv, Ukraine
bChristian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry,
Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Received 23 August 2006; revised 1 November 2006; accepted 16 November 2006
Available online 11 December 2006
Abstract—The reactions of 3-substituted 5-aminopyrazoles with arylidenepyruvic acids and their synthetic precursors, pyruvic acid and
aromatic aldehydes, were studied. Several different reaction pathways for these cyclocondensation reactions were established depending
on the reaction conditions and building block selection. The formation of pyrazolo[3,4-b]pyridine-6-carboxylic acids as major products
and related compounds was discussed from the mechanistic point of view.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
multicomponent reactions of pyruvic acid leading to hetero-
cycles have rarely been investigated. Among those are
publications devoted to the treatment of pyruvic acid
with aromatic amines and aldehydes yielding either quino-
linecarboxylic acids6 or pyrrolidines.7 Multicomponent
reactions of pyruvic acid with aminoazoles have so far not
been described.
Cyclocondensations of aminoazoles and aminoazines with
a,b-unsaturated ketones or their synthetic precursors—
aldehydes and ketones containing at least two active
hydrogen atoms—are the most widespread and investigated
pathways to fused dihydroazaheterocycles.1 In most cases,
both types of reaction pathways, i.e., a sequential protocol
involving the initial synthesis of the a,b-unsaturated
compounds and the three-component reaction, yield the
same products.2 However, in rare cases the direct multi-
component procedure may lead to the formation of different
products,3 connected to the complex reaction mechanisms of
these transformations.3b,c
Previously we reported2b,c two alternative synthetic
pathways to fused pyrimidinecarboxylic acids: by treatment
of 3-amino-1,2,4-triazole, 5-aminotetrazole and 2-amino-
benzimidazole with either arylidenepyruvic acids2b or with
pyruvic acid and aldehydes2c (Scheme 1). At that time
we noted that these three-component reactions carried out
in refluxing DMF were not regioselective and yielded two
isomers.
Reactions of pyruvic acid derivatives with dinucleophiles
have been applied for the synthesis of various types of
heterocycles since the beginning of the last century. Among
those, reactions involving acetyl-4 and arylidenepyruvic2b,5
acids have been studied intensively. On the other hand,
Our interest in pyridine and pyrimidine heterocycles con-
taining fused pyrazole rings is mainly caused by the known
biological activity of these systems reported in the litera-
ture.8 On the other hand, reactions of the 5-aminopyrazole
nucleus, having at least three nucleophilic centres, with
pyruvic acid derivatives, which also possess several reactive
centres, can lead in several directions and are therefore
of interest from the point of view of their chemo- and
regioselectivity.
Keywords: Heterocycles; Cyclocondensation; Multicomponent reactions;
Microwave-assisted organic synthesis; Pyruvic acid derivatives; 5-Amino-
pyrazoles.
* Corresponding author. Tel.: +380 57 341 01 91; fax: +380 57 340 93 43;
e-mail: chebanov@isc.kharkov.com
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.048

1230
V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
NH
Ar
O
O
NH2
Me
N
Ar-CHO
MeOH/KOH
- H2O
N
Ar
OH
OH
O
DMF, Δ
-H2O
N
O
N
H
O
OH
Ar
N
N
AcOH, Δ
N
N
X
O
−2H2O
N
H
OH
O
N
X
NH
Me
Ar-CHO
OH
+
+
NH2
N
O
Ar
Ar
N
N
DMF, Δ
N
X = CH, N
+
N
O
O
-2H2O
N
N
H
N
H
OH
OH
Scheme 1.
2. Results and discussion
procedures.10a,b Azomethine 22 was obtained as reported
in the literature.10c
In this article, we disclose our results on the condensation
reactions of 1-, 3- or 4-substituted 5-aminopyrazoles with
both (i) arylidenepyruvic acids and (ii) with their synthetic
precursors—pyruvic acids and aromatic aldehydes—leading
to fused pyridine or pyrimidine carboxylic acids using
conventional thermal or microwave heating conditions.
2.1. Reactions involving arylidenepyruvic acids
In the course of our investigations we found that refluxing on
an oil bath of equimolar mixtures of 5-amino-3-methylpyr-
azole 1 with unsaturated acids 4a,c in DMF or acetic acid
led to the formation of a pyridine ring. Addition of EtOH
to the reaction mixture allowed to isolate 4-aryl-3-methyl-
pyrazolo[3,4-b]pyridine-6-carboxylic acids 5a,b in satisfac-
tory yields (Table 1). It should be noted that heterocyclic
products in these reactions were not isolable as dihydro-
derivatives, which indicate the high propensity of the ex-
pected 4-aryl-3-methyl-4,7-dihydropyrazolo[3,4-b]pyridine
intermediates to oxidation.
The starting a,b-unsaturated acids 4a–c were synthesized
according to the known literature procedures by reaction
of aromatic aldehydes and pyruvic acid in an aqueous
methanolic solution of potassium hydroxide,9 and were
subsequently used directly without additional purification.
3-Substituted 5-aminopyrazoles 1, 2, 3a,b and 5-amino-N-
phenylpyrazole-4-carboxamides 10a,b were either commer-
cially available (amine 1) or synthesized using published
Table 1. Reactions of 5-aminopyrazoles with arylidenepyruvic acids (Scheme 2)
Building blocks
Product
Aminopyrazole
R
Acid
Compound
R1
Compound
R2
Compound
Yield (%)
1
1
2
2
2
2
3a
3a
3a
3a
3b
3b
3b
3b
11a
11b
11b
11b
11b
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
C6H5
H
H
4a
4c
4a
4c
4a
4c
4a
4b
4c
4b
4a
4b
4c
4c
4c
4a
4b
4c
4d
C6H5
4-CH3O–C6H4
C6H5
4-CH3O–C6H4
C6H5
4-CH3O–C6H4
C6H5
4-Cl–C6H4
4-CH3O–C6H4
4-Cl–C6H4
C6H5
4-Cl–C6H4
4-CH3O–C6H4
4-CH3O–C6H4
4-CH3O–C6H4
C6H5
4-Cl–C6H4
4-CH3O–C6H4
4-CH3–C6H4
5a
5b
6a
6b
7a
7b
8a
8b
8c+9c
10b
8d
8e
8f+10f
9f
12a
12b
12c
12d
12e
38a
42a
C6H5
C6H5
C6H5
C6H5
H
H
H
H
H
H
H
H
—
—
—
—
—
39b
48b
68a
72a
75a
78c
C6H5
C6H5
52a and 26a
31a
4-Br–C6H4
4-Br–C6H4
4-Br–C6H4
4-Br–C6H4
C6H5
4-C2H5O–C6H4
4-C2H5O–C6H4
4-C2H5O–C6H4
4-C2H5O–C6H4
65a
76a
48a and 22a
56c
68a
68a
72a
65a
68a
a
Refluxing in HOAc.
Refluxing in DMF.
Refluxing in HOAc under nitrogen atmosphere.
b
c

V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
1231
Refluxing of 5-amino-3-methyl-1-phenylpyrazole 2 with
arylidenepyruvic acids 4a,c in DMF also yielded hetero-
aromatized 4-aryl-3-methyl-1-phenylpyrazolo[3,4-b]pyr-
idine-6-carboxylic acids 6a,b, however, treatment in
boiling acetic acid allowed us to isolate the corresponding
dihydro analogs 7a,b accompanied by only small amounts
of the aromatized heterocycles 6a,b. Upon exposure to
atmospheric conditions dihydropyridines 7a,b very easily
oxidized to pyridines 6a,b.
with small traces of pyridine derivative 10c was isolated
(compound 10c was not separated from mixture). At that
time, treatment of3bwith unsaturatedacid 4cled toamixture
of 8f (major isomer) and 10f (minor isomer), whereas dihy-
dropyridine derivative 9f was obtained as the single product
in the same reaction under nitrogen atmosphere (Table 1).
When the nucleophilic position 4 on the pyrazole ring was
blocked by an N-arylcarboxamide group as in structures
11a,b treatment with acids 4a–d in boiling acetic acid led
to the clean formation of pyrimidine derivatives 12a–e as
the only isolable product (Scheme 2).
Treatment of arylidenepyruvic acids 4a–c with 5-amino-3-
arylpyrazoles 3a,b in most cases was not regioselective and
yielded mixtures of several regioisomers and products of
their heteroaromatization (Scheme 2). Thus, in reactions of
unsaturated acid 4a with amines 3a,b, and of acid 4b with
amine 3b, carboxylic acids 8a,d,e were obtained as pure sin-
gle isomers whereas reaction of acid 4b with amine 3a
yielded pyrazolopyridine 10b. It is interesting that under ni-
trogen atmosphere the reaction of acid 4b and amine 3a pro-
vided dihydropyrimidine 8b. On the other hand, treatment of
pyrazoles 3a,b with unsaturated acid 4c containing
a methoxyaryl group was less selective and led to the forma-
tion of several products: in reaction of amine 3a with acid 4c
a mixture of 2-phenyl-7-(4-methoxyphenyl)-4,7-dihydro-
pyrazolo[1,5-a]pyrimidine-5-carboxylic acids 8c (major
isomer) and 3-phenyl-4-(4-methoxyphenyl)-4,7-dihydropyr-
azolo[3,4-b]pyridine-6-carboxylic acids 9c (minor isomer)
It should be noted that condensation of the unsaturated acids
4a–d with 5-aminopyrazoles 1, 2, 3a,b never yielded iso-
mers with opposite location of the aryl and carboxyl groups
at the pyridine or pyrimidine rings, respectively.
2.2. Three-component reactions involving pyruvic acid
and aldehydes
As it was pointed out in Section 1, both the sequential and
the one-pot multicomponent approach can yield the same
or different reaction products. In the case of 3-amino-
1,2,4-triazole and 5-aminotetrazol, both types of protocols
led to the formation of the same compounds, i.e., 5-aryl-
5,8-dihydroazolo[1,5-a]pyrimidine-7-carboxylic acids.2b,c
R2
H3C
N
AcOH or DMF, Δ
O
OH
N
H
N
-H2O
5a,b; 38-42%
R2
H3C
DMF, Δ
-H2O
N
O
N
N
Ph
OH
R
O
HO
6a,b; 39-48%
R2
N
+
NH2
R2
N
R1
O
H3C
AcOH, Δ
-H2O
N
+
6a,b
1, 2, 3a,b
4a-c
O
N
N
H
Ph
OH
7a,b; 68-72%
R2
R2
R2
N
R
R
N
N
AcOH, Δ
R
N
N
+
+
O
O
O
-H2O
N
N
N
H
N
H
H
H
OH
OH
OH
10b,c,f;
22-31%
9c,f;
26-56%
8a-f;
48-78%
R = Ar
R2
N
O
R
N
N
HOAc, Δ
-H2O
H
O
+
4a-d
N
H
N
N
H
H
N
NH2
OH
R
O
11a,b
12a-e; 68-72%
Scheme 2.

1232
V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
O
OH
R
N
15a-d; 32-42%
16a-d; 36-44%
17a-i; 39-46%
R
O
O
N
N
R2
AcOH, Δ
Me
R2
OH
+
+
R1
N
NH2
-2H2O
H
N
R1
O
X
5-8
1 ,2, 3a-c
13
14a-d,i
12a-e; 46-58%
O
R
N
AcOH, Δ
O
N
OH
H
+
13
+
14a-d
-2H2O
N
N
H
N
NH2
18
X
N
H
R2
H
N
11a,b
R
O
O
O
CH3
R
O
AcOH, Δ
20c-e; 20-25%
21c-e; 18-22%
Me
+
1, 3a
+
14c-e
N
O
CH3
-2H2O
R2
N
N
O
H
19
Scheme 3.
However, we now find that the three-component condensa-
tion of amines 1, 2, 3a–c with pyruvic acid 13 and aromatic
aldehydes 14a–d,i in refluxing acetic acid leads exclusively
to 6-aryl-3-methylpyrazolo[3,4-b]pyridine-4-carboxylic acids
15a–d, 1,6-diaryl-3-methylpyrazolo[3,4-b]pyridine-4-carb-
oxylic acids 16a–d and 3,6-diarylpyrazolo[3,4-b]pyridine-
4-carboxylic acids 17a–i as reaction products, instead
of the anticipated carboxylic acids 5–9 (Scheme 3, Table 2).
The three-component procedures lead exclusively to the
formation of heteroaromatized compounds even under a
nitrogen atmosphere.
Similarly, multicomponent condensation of amines 11a,b
with pyruvic acid and aldehydes led to pyrimidines 12a–e
Table 2. Three-component reactions of 5-aminoazoles (Scheme 3)
Building blocks
Producta
Aminopyrazole
R
Pyruvic acid
derivative
Aldehyde
R2
Compound
R1
Compound
Compound
Yield (%)
1
1
1
1
2
2
2
2
3a
3a
3a
3a
3b
3b
3b
3b
3c
11a
11a
11b
11b
11b
1
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
C6H5
C6H5
C6H5
4-Br–C6H4
4-Br–C6H4
4-Br–C6H4
4-Br–C6H4
4-C2H5–C6H4
C6H5
4-C2H5O–C6H4
4-C2H5O–C6H4
4-C2H5O–C6H4
4-C2H5O–C6H4
CH3
CH3
CH3
C6H5
C6H5
C6H5
H
H
H
H
C6H5
C6H5
C6H5
C6H5
H
H
H
H
H
H
H
H
H
—
—
—
—
—
H
H
H
H
H
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
19
19
19
19
19
19
14a
14b
14c
14d
14a
14b
14c
14d
14a
14b
14c
14d
14a
14b
14c
14d
14i
14c
14a
14b
14c
14d
14c
14d
14e
14c
14d
14e
C6H5
15a
15b
15c
15d
16a
16b
16c
16d
17a
17b
17c
17d
17e
17f
42
39
42
32
38
44
42
36
42
44
42
39
40
45
42
46
44
46
52
58
40
51
25
20
23
21
18
22
4-Cl–C6H4
4-CH3O–C6H4
4-CH3–C6H4
C6H5
4-Cl–C6H4
4-CH3O–C6H4
4-CH3–C6H4
C6H5
4-Cl–C6H4
4-CH3O–C6H4
4-CH3–C6H4
C6H5
4-Cl–C6H4
4-CH3O–C6H4
4-CH3–C6H4
2-CH3O–5-Br–C6H4
4-CH3O–C6H5
C6H5
4-Cl–C6H4
4-CH3O–C6H4
4-CH3–C6H4
4-CH3O–C6H4
4-CH3–C6H4
4-F–C6H4
4-CH3O–C6H4
4-CH3–C6H4
4-F–C6H4
17g
17h
17i
12a
12b
12c
12d
12e
20c
20d
20e
21c
21d
21e
1
1
3a
3a
3a
H
a
Refluxing in HOAc.

V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
1233
(Scheme 3), which were identical to the compounds iso-
lated from the reaction of 11 with arylidenepyruvic acids
(Scheme 2).
thermal reflux conditions (35–45%). Optimal reaction
conditions involved MW irradiation of an equimolar mixture
of starting materials in ethanol/HCl for 10 min at 150 ꢀC. In
this case, the final fused heterocyclic products 15a–d and
17a–d did not require additional purification.
Surprisingly, treatment of 3-substituted 5-aminopyrazoles 1,
2, 3a–c with arylidenepyruvic acids 4a–c and the three-
component reaction of the same amines with pyruvic acids
13 and aldehydes 14a–d,i led to the formation of a different
set of reaction products, which vary in the position of the
acid and R2 substituents.
Gratifyingly, it was also established that the MW-assisted
reaction of ethyl pyruvate 19 with pyrazole 1, 3a and
aldehydes 14c–h in EtOH with acid catalysis allowed not
only to decrease the reaction time from 120 to 10 min and
made recrystallization of the crude product unnecessary,
but also facilitated the isolation and considerably raised
the yields of the target compounds 20c–h and 21c–h (from
18–25% to 35–48%).
We have also established the possibility of using ethyl pyru-
vate 19 instead of pyruvic acid as a building block in the
three-component reaction with amines 1, 3a and aldehydes.
In this case, however, the corresponding pyrazolopyridines
20a–c and 21a–c were isolated in comparatively low yields
(18–25%).
In summary, the advantages of using the MW-assisted three-
component procedure for the synthesis of pyrazolo[3,4-b]-
pyridine-4-carboxylic acids are following: (i) replacement
of acetic acid with ethanol, which allows a simplified
work-up protocol; (ii) a 8–12-fold reduction of the reaction
time; and (iii) a significantly increased product yield.
2.3. Microwave-assisted three-component reactions
As has been amply demonstrated, controlled microwave
(MW) irradiation is a powerful tool for both speeding up
reaction optimizations and for the efficient preparation of
new target structures,11 with numerous examples of micro-
wave-assisted multicomponent condensations for the con-
struction of heterocycles being reported.12
2.4. Structure elucidation
The structures of the heterocyclic compounds synthesized
were established by IR spectroscopy, mass spectrometry,
NMR spectral data and an X-ray diffraction study (for
details, see Section 4).
We therefore also studied the possibility to use MW irradia-
tion for the optimization of the three-component reaction of
3-substituted 5-aminopyrazoles with pyruvic acid (ethyl
pyruvate) and aromatic aldehydes (Table 3).
1
The H NMR spectra of the fused pyridine analogs 5, 15,
17, 20 and 21 exhibit apart from signals for the terminal
substituents and aromatic rings sharp singlets for the CH
groups of the pyridine ring at ca. 8 ppm and broad peaks
due to the NH– and COOH functionalities around 13–
14 ppm.
It was quickly established that the condensations of amino-
azoles 1, 3a with pyruvic acid (13) and aldehydes 14a–d
could be carried out very efficiently under MW conditions,
either in acetic acid or in ethanol in the presence of HCl
as catalyst. Yields for both protocols were similar and
also comparable to the yields obtained under conventional
1
Similarly, the H NMR spectra of 2,7-diaryl-4,7-dihydro-
pyrazolo[1,5-a]pyrimidine-5-carboxylic acids 8a–f exhibit
Table 3. Microwave-assisted three-component reactions
Building blocks
Producta
Aminopyrazole
R
Pyruvic acid
derivative
Aldehyde
Compound
R1
Compound
R2
Compound
Yield (%)
1
1
1
1
3a
3a
3a
3a
1
1
1
1
1
CH3
CH3
CH3
CH3
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
13
13
13
13
13
13
13
13
19
19
19
19
19
19
19
19
19
19
19
19
14a
14b
14c
14d
14a
14b
14c
14d
14c
14d
14e
14f
14g
14h
14c
14d
14e
14f
C6H5
15a
15b
15c
15d
17a
17b
17c
17d
20c
20d
20e
20f
20g
20h
21c
21d
21e
21f
45
42
43
35
43
44
42
41
42
42
47
45
40
35
43
48
48
45
41
36
4-Cl–C6H4
4-CH3O–C6H4
4-CH3–C6H4
C6H5
4-Cl–C6H4
4-CH3O–C6H4
4-CH3–C6H4
4-CH3O–C6H4
4-CH3–C6H4
4-F–C6H4
4-Br–C6H4
3-Cl–C6H4
2-Cl–C6H4
4-CH3O–C6H4
4-CH3–C6H4
4-F–C6H4
4-Br–C6H4
3-Cl–C6H4
2-Cl–C6H4
1
CH3
3a
3a
3a
3a
3a
3a
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
14g
14h
21g
21h
a
Reaction in EtOH/HCl under MW irradiation for 10 min at 150 ꢀC.

1234
V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
˚
doublet of doublets for protons at positions 6 (w5.8 and
6.2 ppm, 3Jw4.2 Hz, 4Jw1.5 Hz with NH of pyrimidine
ring) and a doublet of the CH proton at position 7
and the C(4)–C(5) 1.366(6) A bond is shortened as com-
pared to their mean value for a pyridine ring13 1.380 A).
˚
The carboxylic group at the C(4) atom and the aromatic
ring of the substituent at the C(2) atom are not coplanar
with respect to the bicyclic fragment (the C(3)–C(4)–
C(14)–O(1) and the C(3)–C(2)–C(15)–C(20) torsion angles
are ꢁ31.9(7)ꢀ and ꢁ40.3(8)ꢀ, respectively). Such an
arrangement of these substituents is caused, probably, by
the repulsion between them (the shortened intramolecular
3
(w5.8 ppm, Jw4.2 Hz). The presence in spectra of a sharp
singlet for the pyrazole CH atw6 ppm shows that treatment
did not affect this nucleophilic centre and confirms the for-
mation of the pyrimidine ring. The resonances for the pyrim-
idine NH and COOH groups are present in the spectra at
approximately 9.3 and 12.5 ppm, respectively.
˚
contacts C(14)/C(20) 3.34 A (the sum of the correspond-
ing van der Waals radii14 is 3.42 A), O(1)/C(20) 2.94 A
˚
˚
The signals for the C]CH–CH fragment of the pyridine
nucleus in dihydroderivatives 7a,b and 9a–c,e,f are shifted
upfield as compared to compounds 8 and 12, and the ethyl-
ene proton (doublet) does not show coupling with the amino
group. The presence of a NH resonance signal for the pyr-
azole nucleus (for compound 9) and the absence of a singlet
for the pyrazole CH group confirmed the formation of the
pyridine but not pyrimidine ring.
˚
(3.00 A)).
The benzene ring of the substituent at the C(6) atom is turned
relatively the mean plane of the bicyclic fragment (the C(5)–
C(6)–C(7)–C(8) torsion angle is 34.9(7)ꢀ). It can be assumed
that such orientation of the substituent is stabilized by
the attractive interactions C(5)–H(5)/O(3) 2.28 A, and the
C(12)–H(12)/N(1) 2.57 A. The methoxy group and the
˚
˚
The structures of compounds 17a–i were finally proven by
an X-ray analysis (Fig. 1). Here it was also established that
benzene ring are almost coplanar (the C(13)–O(3)–C(8)–
C(9) torsion angle is 6.2(7)ꢀ) despite of the repulsion
between the methyl group and atoms of the aromatic ring
˚
the bicyclic fragment is a planar within 0.02 A. The bond
alternation is observed within the pyridine ring (the C(3)–
˚
(the shortened intramolecular contacts H(9)/C(13) 2.51 A
˚
C(4) 1.419(6) A and C(5)–C(6) 1.415(6) A bonds are longer
˚
˚
˚
˚
˚
(2.87 A), H(9)/H(13) 2.28 A (2.34 A), H(13b)/C(9)
˚
˚
˚
2.71 A (2.87 A), H(13c)/C(9) 2.79 A (2.87 A)).
To establish the relative location of substituents in the other
fused pyridine or pyrimidine derivatives, several additional
experiments were carried out. Thus, compound 9f was hetero-
aromatized in NMR tubes in DMSO-d6, which confirmed
that the products of oxidation have 1H NMR spectra different
from structures 17f and equivalent to 10f. On this basis, and
with regard to the additional spectral data, the structure of
3,4-diaryl-4,7-dihydropyrazolo[3,4-b]pyridine-6-carboxylic
acids were assigned to 9c,f.
The locations of the substituents in pyrazolopyridines and
pyrazolopyrimidines 5–9, 16, 17 were also derived on the
basis of NOE experiments (Fig. 2). Thus, the presence or
absence of an NOE between specific protons allowed to
establish the structures for these compounds unequivocally.
Figure 1. Molecular structure (X-ray diffraction data) of 3-(4-ethylphenyl)-
6-(5-bromo-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic
acid (17i).
NOE
NOE
NOE
H
N
H
H
H
H3C
H3C
H3C
N
O
N
O
NOE
N
O
NOE
N
N
H
N
N
N
H
NOE
NOE
H
OH
OH
H
OH
5
6
7
O
OH
NOE
H
NOE
H
H
H
H
N
N
H
N
O
N
R
N
N
H
H
NOE
OH
H
H
H
H
N
NOE
O
NOE
N
H
N
H
OH
8
9
16, 17
Figure 2. NOE experiments for structure determinations.

V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
1235
R
15a-d
16a-d
17a-i
13, [O]
N
R2
1, 2, 3a-c
+
14a-d,i
N
-H2O
-H2O
N
R1
A
Ph
12, [O]
-H2O
N
N
H
Ph
17a
N
22
Scheme 4.
1
The similarity of the H NMR spectra between dihydro-
pyrimidines 12a–d and compounds 8a–f allowed to assign
them the structure of 7-aryl-3-(arylcarbamoyl)-4,7-dihydro-
pyrazolo[1,5-a]pyrimidine-5-carboxylic acids.
initial nucleophilic attack of the endocyclic NH of the
aldehyde carbonyl group (intermediate B, Scheme 5).
O
R
N
H
13
2.5. Mechanistic aspects
12a-e
N
11a,b
+ 14a-d
NH2
-2H2O
N
The different reaction pathways experienced in the trans-
formation studies in the present investigation can be ratio-
nalized from the mechanistic point of view.
R2
OH
B
Scheme 5.
It is most likely that the three-component condensation of
3-substituted 5-aminopyrazoles 1, 2, 3a,b with pyruvic
acid (or ethyl pyruvate) and aromatic aldehydes proceeds
through initial formation of the corresponding azomethine
(intermediate A) with subsequent heterocyclization with
pyruvic acid yielding the observed pyridine carboxylic acids
15–17 as products (Scheme 4). The condensation of inde-
pendently synthesized azomethine 22 with pyruvic acid
confirmed this assumption.
For the condensation of 3-methyl-5-aminopyrazoles 1, 2
with arylidenepyruvic acids 4a–c the initial reaction step
possibly involves a nucleophilic attack of the CH group of
the aminopyrazole to the C]C double bond of the unsatu-
rated acid with the formation of Michael adduct C and its
subsequent cyclization to pyridines 5–7 (Scheme 6). On
the other hand, in the case of 3-aryl-5-aminopyrazoles
3a–c the C]C double bond of the unsaturated acid may
be attacked by both the endocyclic nitrogen atom (interme-
diate D) and (less likely) by the sterically hindered CH group
(intermediate E), leading to the formation of pyrazolopyr-
imidines or mixtures with pyrimidine derivatives (structures
8 and 9, respectively).
As it was pointed out above, three-component condensations
involving aminopyrazoles 11a,b leading to the formation of
dihydropyrimidine derivatives 12a–e do not proceed through
azomethine formation. This is most likely the result of the
influence of the carboxamide fragment on the nucleophilic-
ity of the amino group via p-electron withdrawing effect and
the formation of an intramolecular hydrogen bond (shown
As it was pointed out above, the yields of pyridine deriva-
tives 15–17, 20, 21 were always lower than 50%, both under
atmospheric and inert conditions. Participation of one of the
intermediates in the mechanistic pathway of the oxidation
1
by the H NMR spectrum of amines 11a,b, having non-
equivalent NH2 protons). Here, the reaction is likely to
proceed via a different pathway, for example, through
[O]
5a-c
6a,b
O
OH
R2
H3C
N
O
1, 2
+ 4a-c
- H2O
NH2
N
R1
7a,b
C
9c,f
O
OH
R2
R2
Ar
O
O
N
OH
8a-f
3a,b + 4a-c
N
-H2O
Ar
-H2O
N
NH2
N
O
NH2
H
[O]
10b,c,f
D
E
Scheme 6.

1236
V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
process may be a reason for this fact. Unfortunately, our
attempts to establish the composition of the mother liquor
after isolation of the target compounds by preparative
HPLC were unsuccessful.
C, 66.40; H, 4.38; N, 16.59. Found: C, 66.51; H, 4.25; N,
16.61.
4.1.1.2. 4-(4-Methoxyphenyl)-3-methyl-1H-pyrazolo-
[3,4-b]pyridine-6-carboxylic acid (5b). Yield: 130 mg
1
(42%) of yellow crystals, mp>300 ꢀC. H NMR (DMSO-
3. Conclusions
d6) d 2.24 (s, 3H, CH3), 3.83 (s, 3H, OCH3) 7.0–7.5 (m,
4H, ArH), 7.62 (s, 1H, 5-H), 13.60 (s, 1H, NH). Anal. Calcd
for C15H13N3O3: C, 63.60; H, 4.63; N, 14.83. Found: C,
63.71; H, 4.50; N, 14.87.
The sequential and multicomponent reactions of 1-, 3- or
4-substituted 5-aminopyrazoles with arylidenepyruvic acids
or their synthetic precursors were studied. Several different
reaction pathways for these cyclocondensation reactions
including the formation of pyrazolo[3,4-b]pyridine-6-carb-
oxylic acids, pyrazolo[1,5-a]pyrimidine-5-carboxylic acids
and pyrazolo[3,4-b]pyridine-4-carboxylic acids were estab-
lished depending on the specific reaction conditions and
building block selection. Facile and rapid microwave-assis-
ted procedures for the synthesis of pyrazolo[3,4-b]pyridine-
4-carboxylic acids were elaborated, which allowed a simple
work-up protocol, reduction of the reaction time and a signif-
icant increase in yields. The formation of different reaction
products was discussed from the mechanistic point of view.
4.1.2. General procedure for the synthesis of 1,4-diaryl-3-
methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acids
6a,b. A mixture of 5-amino-3-methyl-1-phenylpyrazole 2
(1.1 mmol) and the appropriate arylidenepyruvic acid 4
(1.1 mmol) in 0.7 mL of DMF was refluxed for 30 min.
After cooling, 5 mL of EtOH was added and the mixture
was allowed to stand overnight. The precipitate formed was
isolated by filtration, crystallized from EtOH and air dried.
4.1.2.1. 3-Methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]-
pyridine-6-carboxylic acid (6a). Yield: 140 mg (39%) of
yellow crystals, mp 268–270 ꢀC. 1H NMR (DMSO-d6)
d 2.21 (s, 3H, CH3), 7.2–8.4 (m, 10H, ArH), 7.75 (s, 1H,
5-H), 13.5 (br s, 1H, COOH). 13C NMR (DMSO-d6) d 14.2,
107.7, 118.3, 121.1, 123.2, 126.3, 126.6, 127.1, 127.7,
134.6, 142.8, 143.1, 144.1, 147.1, 151.0, 166.0. MS (El,
70 eV): m/z (%)¼329 (100%) [M+], 285 (40.3). Anal. Calcd
for C20H15N3O2: C, 72.94; H, 4.59; N, 12.76. Found: C,
73.02; H, 4.47; N, 12.80.
4. Experimental
4.1. General
Melting points of all compounds synthesized were deter-
mined with a Kofler or Gallenkamp melting point apparatus.
The NMR spectra were recorded in DMSO-d6 at 360 MHz
(90.5 MHz for 13C) with a Bruker AMX-360 and at
200 MHz (50 MHz for 13C) with a Varian Mercury VX-200
spectrometer. The MS spectra were measured on a GC–MS
Varian 1200L (ionizing voltage 70 eV) instrument. IR spec-
tra were recorded in KBr pellets with a Perkin–Elmer
Spectrum One FTIR spectrometer. Elemental analysis was
realized on EuroVector EA-3000.
4.1.2.2. 4-(4-Methoxyphenyl)-3-methyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-6-carboxylic acid (6b). Yield:
190 mg (48%) of yellow crystals, mp 262–264 ꢀC. 1H
NMR (DMSO-d6) d 2.32 (s, 3H, CH3), 3.85 (s, 3H, OCH3)
7.10–8.33 (m, 10H, ArH), 7.75 (s, 1H, 5-H), 13.5 (br s,
1H, COOH). Anal. Calcd for C21H17N3O3: C, 70.18; H,
4.77; N, 11.99. Found: C, 70.21; H, 4.68; N, 12.02.
All microwave experiments were performed using the
EmrysÔ Creator EXP and EmrysÔ Initiator 8 synthesizers
from Biotage AB (Uppsala, Sweden) possessing a single-
mode microwave cavity producing controlled irradiation at
2.45 GHz. Experiments were carried out in sealed micro-
wave process vials utilizing the high absorbance level. Reac-
tion time reflects irradiation times at the set reaction
temperature (fixed hold times).
4.1.3. General procedure for the synthesis of 1,4-diaryl-3-
methyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-6-carb-
oxylic acids 7a,b. A mixture of 5-amino-3-methyl-1-
phenylpyrazole 2 (1.1 mmol) and the appropriate arylidene-
pyruvic acid 4 (1.1 mmol) in 3 mL of acetic acid was
refluxed for 30 min. The mixture was allowed to stand over-
night and the precipitate formed was isolated by filtration.
The by-products 6 were removed by crystallization from
EtOH.
4.1.1. General procedure for the synthesis of 4-aryl-3-
methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acids
5a,b. A mixture of 5-amino-3-methylpyrazole 1 (1.1 mmol)
and the appropriate arylidenepyruvic acid 4 (1.1 mmol) in
1 mL of acetic acid was refluxed for 1 h. After cooling,
5 mL of EtOH was added and the mixture was allowed to
stand overnight. The precipitate formed was isolated by filtra-
tion, crystallized from EtOH and air dried.
4.1.3.1. 3-Methyl-1,4-diphenyl-4,7-dihydro-1H-pyrazolo
[3,4-b]pyridine-6-carboxylic acid (7a). Yield: 250 mg (68%)
of yellow crystals, mp 222–224 ꢀC. IR (KBr): 3264, 1708,
1
1596, 1252. H NMR (DMSO-d6) d 1.75 (s, 3H, CH3), 4.91
(d, J¼4 Hz, 1H, 4-H), 5.73 (d, J¼4 Hz, 1H, 5-H), 7.1–7.7
(m, 10H, ArH), 13.5 (br s, 2H, NH+COOH). 13C NMR
(DMSO-d6) d 15.1, 44.2, 99.1, 115.6, 123.7, 124.0, 125.1,
128.1, 129.2, 129.1, 131.4, 138.6, 141.8, 145.15, 145.7,
169.3. Anal. Calcd for C20H17N3O2: C, 72.49; H, 5.17; N,
12.68. Found: C, 72.52; H, 5.06; N, 12.71.
4.1.1.1. 3-Methyl-4-phenyl-1H-pyrazolo[3,4-b]pyr-
idine-6-carboxylic acid (5a). Yield: 105 mg (38%) of yel-
1
low crystals, mp>300 ꢀC. H NMR (DMSO-d6) d 2.19 (s,
3H, CH3), 7.1–7.6 (m, 5H, ArH), 7.65 (s, 1H, 5-H), 12.0
(br s, 1H, COOH), 13.68 (s, 1H, NH). 13C NMR (DMSO-
d6) d 12.4, 110.3, 119.0, 124.6, 125.8, 128.3, 140.1, 143.3,
144.0, 146.5, 148.2, 166.3. Anal. Calcd for C14H11N3O2:
4.1.3.2. 4-(4-Methoxyphenyl)-3-methyl-1-phenyl-4,7-
dihydro-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (7b).
Yield: 290 mg (72%) of yellow crystals, mp 238–240 ꢀC.

V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
1237
1H NMR (DMSO-d6) d 1.75 (s, 3H, CH3), 3.71 (s, 3H,
OCH3), 4.85 (d, J¼4.3 Hz, 1H, 4-H), 5.70 (d, J¼
4.3 Hz, 1H, 5-H), 6.8–7.6 (m, 9H, ArH), 13.2 (br s, 2H,
NH+COOH). Anal. Calcd for C21H19N3O3: C, 69.79; H,
5.30; N, 11.63. Found: C, 69.84; H, 5.20; N, 11.64.
(d, J¼4.3 Hz, 1H, 7-H), 7.14–7.65 (m, 8H, ArH), 9.38 (s,
NH), 12.70 (br s, 1H, COOH). Anal. Calcd for
C19H13BrClN3O2: C, 52.99; H, 3.04; N, 9.76. Found: C,
53.01; H, 2.98; N, 9.80.
4.1.4.6.
2-(4-Bromophenyl)-7-(4-methoxyphenyl)-
4.1.4. General procedure for the synthesis of 2,7-diaryl-
4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic
acids 8a–c,d–f, 3,4-diaryl-4,7-dihydro-1H-pyrazolo[3,4-
b]pyridine-6-carboxylic acids 9c,f and 10b,f. A mixture
of the appropriate 5-amino-3-arylpyrazole 3 (1.1 mmol)
4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid
(8f). Yield: 220 mg (48%) of yellowish crystals, mp
1
214–216 ꢀC. H NMR (DMSO-d6) d 3.7 (s, 3H, OCH3),
d 5.66 (dd, J¼4.3, 1.9 Hz, 1H, 6-H), 6.0 (s, 1H, 3-H),
6.13 (d, J¼4.3 Hz, 1H, 7-H), 6.8–7.6 (m, 8H, ArH),
9.27 (d, J¼1.9 Hz, NH). Anal. Calcd for C20H16BrN3O3:
C, 56.35; H, 3.78; N, 9.86. Found: C, 56.38; H, 3.65; N,
9.82.
and of the corresponding arylidenepyruvic acid
4
(1.1 mmol) in 3 mL of acetic acid was refluxed for 30 min.
After cooling, the precipitate formed was filtered and
if needed recrystallized from EtOH. The acids 8c,f were
isolated from 9c and 10f by crystallization from EtOH.
Compounds 8b and 9f were obtained using the same proce-
dure under a nitrogen atmosphere.
4.1.4.7. 4-(4-Methoxyphenyl)-3-phenyl-4,7-dihydro-
1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (9c). Yield:
100 mg (26%) of yellow crystals, mp 265–267 ꢀC. 1H NMR
(DMSO-d6) d 3.63 (s, 3H, OCH3), 5.11 (d, J¼4.9 Hz, 1H,
4-H), 5.54 (d, J¼4.9 Hz, 1H, 5-H), 6.68–7.47 (m, 9H, ArH),
7.78 (s, NH), 14.22 (br s, NH), 12.78 (br s, 1H, COOH).
Anal. Calcd for C20H17N3O3: C, 69.15; H, 4.93; N, 12.10.
Found: C, 69.18; H, 4.82; N, 12.12.
4.1.4.1. 2,7-Diphenyl-4,7-dihydropyrazolo[1,5-a]pyr-
imidine-5-carboxylic acid (8a). Yield: 260 mg (75%) of yel-
lowish crystals, mp 215–217 ꢀC. IR (KBr): 3350, 1710, 1597.
1H NMR (DMSO-d6) d 5.69 (dd, 3J¼4.5, 1.7 Hz, 1H, 6-H),
6.01 (s, 1H, 3-H), 6.20 (d, J¼4.5 Hz, 1H, 7-H), 7.1–7.7 (m,
10H, ArH), 9.28 (d, J¼1.7 Hz, NH), 12.53 (br s, 1H,
COOH). 13C NMR (DMSO-d6) d 61.1, 83.0, 117.1, 125.4,
127.7, 128.5, 130.9, 132.1, 133.8, 134.7, 138.3, 139.1,
141.1, 147.9, 166.3. Anal. Calcd for C19H15N3O2: C, 71.91;
H, 4.76; N, 13.24. Found: C, 72.02; H, 4.65; N, 13.27.
4.1.4.8. 3-(4-Bromophenyl)-4-(4-methoxyphenyl)-4,7-di-
hydro-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (9f).
Yield: 260 mg (56%) of yellow crystals, mp 276–278 ꢀC. IR
1
(KBr): 3480, 1711, 1666, 1605, 1509. H NMR (DMSO-d6)
d 3.64 (s, 3H, OCH3), 5.12 (d, J¼4.7 Hz, 1H, 4-H), 5.53 (d,
J¼4.7 Hz, 1H, 5-H), 6.7–7.5 (m, 8H, ArH), 7.86 (s, NH),
14.3 (br s, NH), 12.85 (br s, 1H, COOH). Anal. Calcd for
C20H16BrN3O3: C, 56.35; H, 3.78; N, 9.86. Found: C, 56.39;
H, 3.65; N, 9.75.
4.1.4.2. 7-(4-Chlorophenyl)-2-phenyl-4,7-dihydropyr-
azolo[1,5-a]pyrimidine-5-carboxylic acid (8b). Yield:
1
300 mg (78%) of yellowish crystals, mp 216–218 ꢀC. H
NMR (DMSO-d6) d 5.67 (dd, J¼4.1, 1.3 Hz, 1H, 6-H),
6.01 (s, 1H, 3-H), 6.23 (d, J¼4.1 Hz, 1H, 7-H), 7.15–7.7
(m, 9H, ArH), 9.32 (d, J¼1.7 Hz, NH), 12.5 (br s, 1H,
COOH). Anal. Calcd for C19H14ClN3O2: C, 64.87; H,
4.01; N, 11.94. Found: C, 64.83; H, 3.90; N, 11.97.
4.1.4.9. 4-(4-Chlorophenyl)-3-phenyl-1H-pyrazolo[3,4-b]-
pyridine-6-carboxylic acid (10b). Yield: 120 mg (31%) of
yellowish crystals, mp>300 ꢀC. 1H NMR (DMSO-d6)
d 7.80 (s, 1H, 5-H), 7.0–7.4 (m, 9H, ArH), 14.3 (br s, 1H,
NH), 13.9 (br s, 1H, COOH). Anal. Calcd for C19H12ClN3O2:
C, 65.24; H, 3.46; N, 12.01. Found: C, 65.31; H, 3.36; N,
12.05.
4.1.4.3. 7-(4-Methoxyphenyl)-2-phenyl-4,7-dihydro-
pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (8c). Yield:
1
200 mg (52%) of yellowish crystals, mp 214–216 ꢀC. H
NMR (DMSO-d6) d 3.69 (s, 3H, OCH3), d 5.67 (dd,
J¼4.2, 1.8 Hz, 1H, 6-H), 5.98 (s, 1H, 3-H), 6.13 (d, J¼
4.2 Hz, 1H, 7-H), 6.82–7.68 (m, 9H, ArH), 9.22 (d, J¼
1.8 Hz, NH), 12.56 (br s, 1H, COOH). Anal. Calcd for
C20H17N3O3: C, 69.15; H, 4.93; N, 12.10. Found: C,
69.16; H, 4.85; N, 12.13.
4.1.4.10. 3-(4-Bromophenyl)-4-(4-methoxyphenyl)-1H-
pyrazolo[3,4-b]pyridine-6-carboxylic acid (10f). Yield:
1
100 mg (22%) of yellow crystals, mp>300 ꢀC. H NMR
(DMSO-d6) d 3.75 (s, 3H, OCH3), 7.78 (s, 1H, 5-H), 6.7–
7.4 (m, 8H, ArH), 14.31 (br s, 1H, NH), 13.95 (br s, 1H,
COOH). Anal. Calcd for C20H14BrN3O3: C, 56.62; H, 3.33;
N, 9.90. Found: C, 56.69; H, 3.22; N, 9.87.
4.1.4.4. 2-(4-Bromophenyl)-7-phenyl-4,7-dihydropyr-
azolo[1,5-a]pyrimidine-5-carboxylic acid (8d). Yield:
4.1.5. General procedures for the synthesis of 7-aryl-3-
(arylcarbamoyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-
5-carboxylic acid 12a–e. Method A: A mixture of the
appropriate 5-amino-N-aryl-1H-pyrazole-4-carboxamide 11
(1 mmol) and the corresponding arylidenepyruvic acid 4
(1 mmol) was refluxed in 5 mL of acetic acid for 10–
20 min until a solid started to precipitate. After cooling,
the crystals formed were removed by filtration, washed
with EtOH and air dried. If required, products were crystal-
lized from EtOH.
1
280 mg (65%) of yellowish crystals, mp 222–225 ꢀC. H
3
4
NMR (DMSO-d6) d 5.69 (dd, J¼4.2 Hz, J¼1.8 Hz, 1H,
6-H), 6.02 (s, 1H, 3-H), 6.19 (d, J¼4.2 Hz, 1H, 7-H), 7.1–
7.6 (m, 9H, ArH), 9.32 (s, 1H, NH), 12.58 (br s, 1H,
COOH). Anal. Calcd for C19H14BrN3O2: C, 57.59; H,
3.56; N, 10.60. Found: C, 57.62; H, 3.42; N, 10.62.
4.1.4.5. 2-(4-Bromophenyl)-7-(4-chlorophenyl)-4,7-
dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid (8e).
Yield: 360 mg (76%) of yellowish crystals, mp 220–
1
222 ꢀC. IR (KBr): 3413, 1710, 1595. H NMR (DMSO-d6)
Method B: A mixture of the appropriate 5-amino-N-aryl-
1H-pyrazole-4-carboxamide 11 (1 mmol), pyruvic acid 13
d 5.68 (dd, J¼4.3, 1.7 Hz, 1H, 6-H), 6.03 (s, 1H, 3-H), 6.22

1238
V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
(1 mmol) and the corresponding aldehyde 14 (1 mmol) was
refluxed in 3 mL of acetic acid for 2 h. After cooling, the
crystals precipitated were removed by filtration, washed
with EtOH and air dried. If required, products were crystal-
lized from EtOH.
4.1.6. General procedure for the synthesis of 6-aryl-3-
methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids
15a–d and 3,6-diaryl-1H-pyrazolo[3,4-b]pyridine-4-
carboxylic acids 17a–i. Conventional method C: A mixture
of the appropriate 5-aminopyrazole 1 or 3a (2 mmol),
pyruvic acid 13 (2 mmol) and the corresponding aromatic
aldehyde 14 (2 mmol) in 3 mL of acetic acid was refluxed
for 10–40 min until a solid started to precipitate. After cool-
ing, the crystals formed were removed by filtration, crystal-
lized from EtOH and air dried.
4.1.5.1. 7-(4-Methoxyphenyl)-3-(phenylcarbamoyl)-
4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid
(12a). Yields: 265 mg (68%, method A) and 180 mg (46%,
1
method B) of yellowish crystals, mp 254–256 ꢀC. H NMR
(DMSO-d6) d 3.71 (s, 3H, OCH3), 5.81 (dd, J¼4.1, 1.8 Hz,
1H, 6-H), 6.17 (d, J¼4.1 Hz, 1H, 7-H), 6.8–7.7 (m, 9H,
ArH), 8.06 (br s, 1H, 2-H), 8.39 (d, J¼1.8 Hz, 1H,
NH), 9.76 (s, 1H, CONH). Anal. Calcd for C21H18N4O4:
C, 64.61; H, 4.65; N, 14.35. Found: C, 64.63; H, 4.57; N,
14.37.
Microwave-assisted method D: A mixture of the appropriate
5-aminopyrazole 1 or 3a (1.3 mmol), pyruvic acid 13
(1.3 mmol) and the corresponding aromatic aldehyde 14
(1.3 mmol) in 1 mL of EtOH with two drops of HCl was ir-
radiated under sealed vessel microwave conditions at 150 ꢀC
for 10 min in a 5 mL microwave process vial. After cooling,
the crystals formed were removed by filtration, washed with
EtOH and air dried.
4.1.5.2. 3-[(4-Ethoxyphenyl)carbamoyl]-7-phenyl-4,7-
dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid (12b).
Yields: 275 mg (68%, method A) and 210 mg (52%, method
B) of yellowish crystals, mp 266–268 ꢀC. IR (KBr): 3400,
4.1.6.1.
3-Methyl-6-phenyl-1H-pyrazolo[3,4-b]pyr-
1
1746, 1722, 1600, 1509. H NMR (DMSO-d6) d 1.3 (t, 3H,
idine-4-carboxylic acid (15a). Yields: 210 mg (42%,
method C) and 150 mg (45%, method D) of yellow crystals,
mp>300 ꢀC. IR (KBr): 3244, 1708, 1592. 1H NMR (DMSO-
d6) d 2.60 (s, 3H, CH3), 7.4–8.2 (m, 5H, ArH), 8.02 (s, 1H,
5-H), 13.55 (br s, 2H, NH+COOH). 13C NMR (DMSO-d6)
d 14.5, 115.1, 119.7, 128.6, 129.0, 131.5, 134.8, 135.2,
142.5, 148.3, 155.7, 167.7. Anal. Calcd for C14H11N3O2:
C, 66.40; H, 4.38; N, 16.59. Found: C, 66.57; H, 4.25; N,
16.54.
OCH2CH3), 3.98 (q, 2H, OCH2CH3), 5.83 (dd, J¼4.1,
1.8 Hz, 1H, 6-H), 6.23 (d, J¼4.1 Hz, 1H, 7-H), 6.8–7.6 (m,
9H, ArH), 8.04 (s, 2-H), 8.42 (d, J¼1.8 Hz, 1H, NH), 9.68
(s, 1H, CONH). Anal. Calcd for C22H20N4O4: C, 65.34; H,
4.98; N, 13.85. Found: C, 65.38; H, 4.87; N, 13.86.
4.1.5.3. 5-(4-Chlorophenyl)-3-[(4-ethoxyphenyl)carb-
amoyl]-4,5-dihydropyrazolo[1,5-a]pyrimidine-7-carboxy-
lic acid (12c). Yields: 310 mg (72%, method A) and 250 mg
(58%, method B) of yellowish crystals, mp 267–269 ꢀC. IR
(KBr): 3393, 3361, 1755, 1721, 1603, 1510. 1H NMR
(DMSO-d6) d 1.3 (t, 3H, OCH2CH3), 3.98 (q, 2H,
OCH2CH3), 5.82 (d, J¼4.2 Hz, 1H, 6-H), 6.27 (dd, J¼4.1,
1.7 Hz, 1H, 7-H), 6.8–7.6 (m, 8H, ArH), 8.05 (s, 1H, 2-H),
8.43 (d, J¼1.7 Hz, 1H, NH), 9.68 (s, 1H, CONH). Anal.
Calcd for C22H19ClN4O4: C, 60.21; H, 4.36; N, 12.77.
Found: C, 60.25; H, 4.24; N, 12.80.
4.1.6.2. 6-(4-Chlorophenyl)-3-methyl-1H-pyrazolo-
[3,4-b]pyridine-4-carboxylic acid (15b). Yields: 220 mg
(39%, method C) and 160 mg (42%, method D) of yellow
crystals, mp>300 ꢀC. IR (KBr): 3172, 1716, 1592. 1H
NMR (DMSO-d6) d 2.59 (s, 3H, CH3), 7.53–8.25 (m, 4H,
ArH), 7.98 (s, 1H, 5-H), 13.58 (br s, 2H, NH+COOH).
Anal. Calcd for C14H10ClN3O2: C, 58.42; H, 3.50; N,
14.61. Found: C, 58.36; H, 3.35; N, 14.58.
4.1.5.4. 3-[(4-Ethoxyphenyl)carbamoyl]-7-(4-methoxy-
phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxy-
lic acid (12d). Yields: 290 mg (68%, method A) and 170 mg
(40%, method B) of yellowish crystals, mp 267–269 ꢀC. IR
(KBr): 3388, 1720, 1599, 1509. 1H NMR (DMSO-d6) d 1.3
(t, 3H, OCH2CH3), 3.98 (q, 2H, OCH2CH3), 3.72 (s, 3H,
OCH3), 5.81 (dd, J¼4.1, 1.8 Hz, 1H, 6-H), 6.17 (d, J¼
4.1 Hz, 1H, 7-H), 6.8–7.6 (m, 8H, ArH), 8.02 (s, 1H, 2-H),
8.4 (d, J¼1.8 Hz, 1H, NH), 9.66 (s, 1H, CONH). Anal. Calcd
for C23H22N4O5: C, 63.59; H, 5.10; N, 12.90. Found: C,
63.61; H, 5.00; N, 12.92.
4.1.6.3. 6-(4-Methoxyphenyl)-3-methyl-1H-pyrazolo-
[3,4-b]pyridine-4-carboxylic acid (15c). Yields: 240 mg
(42%, method C) and 160 mg (43%, method D) of yellow
crystals, mp>300 ꢀC. IR (KBr): 3248, 1712, 1596. 1H
NMR (DMSO-d6) d 2.58 (s, 3H, CH3), 3.82 (s, 3H,
OCH3), 7.0–8.2 (m, 4H, ArH), 7.95 (s, 1H, 5-H), 13.56 (br
s, 2H, NH+COOH). Anal. Calcd for C15H13N3O3: C,
63.60; H, 4.63; N, 14.83. Found: C, 63.57; H, 4.50; N, 14.87.
4.1.6.4.
3-Methyl-6-p-tolyl-1H-pyrazolo[3,4-b]pyr-
idine-4-carboxylic acid (15d). Yields: 170 mg (32%,
method C) and 120 mg (35%, method D) of yellow crystals,
mp>300 ꢀC. IR (KBr): 3248, 1712, 1592. 1H NMR (DMSO-
d6) d 2.59 (s, 3H, CH3), 2.36 (s, 3H, CH3), 7.3–8.1 (m, 4H,
ArH), 7.97 (s, 1H, 5-H), 13.56 (br s, 2H, NH+COOH).
Anal. Calcd for C15H13N3O2: C, 67.41; H, 4.90; N, 15.72.
Found: C, 67.44; H, 4.79; N, 15.68.
4.1.5.5. 3-[(4-Ethoxyphenyl)carbamoyl)-5-p-tolyl-4,5-
dihydropyrazolo[1,5-a]pyrimidine-7-carboxylic acid (12e).
Yields: 270 mg (65%, method A) and 210 mg (51%, method
B) of yellowish crystals, mp 265–267 ꢀC. IR (KBr): 3416,
1717, 1602, 1510. 1H NMR (DMSO-d6) d 1.3 (t, 3H,
OCH2CH3), 3.98 (q, 2H, OCH2CH3), 2.26 (s, 3H, CH3),
5.80 (dd, J¼4.1, 1.7 Hz, 1H, 6-H), 6.18 (d, J¼4.1 Hz, 1H, 7-
H), 6.8–7.6 (m, 8H, ArH), 8.02 (s, 1H, 2-H), 8.39 (d,
J¼1.7 Hz, 1H, NH), 9.67 (s, 1H, CONH). Anal. Calcd for
C23H22N4O4: C, 66.02; H, 5.30; N, 13.39. Found: C, 66.07;
H, 5.19; N, 13.42.
4.1.6.5. 3,6-Diphenyl-1H-pyrazolo[3,4-b]pyridine-4-
carboxylic acid (17a). Yields: 265 mg (42%, method C)
and 180 mg (43%, method D) of yellow crystals,
mp>300 ꢀC. IR (KBr): 3268, 1708, 1592. 1H NMR
(DMSO-d6) d 7.4–8.3 (m, 10H, ArH), 7.97 (s, 1H, 5-H),

V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
1239
13.50 (br s, 1H, COOH), 14.13 (s, 1H, NH). 13C NMR
(DMSO-d6) d 114.92, 118.3, 128.7, 128.9, 129.3, 130.1,
130.3, 131.0, 134.1, 135.7, 142.1, 143.6, 147.3, 156.1,
167.5. Anal. Calcd for C19H13N3O2: C, 72.37; H, 4.16; N,
13.33. Found: C, 72.25; H, 4.22; N, 13.36.
Anal. Calcd for C20H14BrN3O2: C, 58.84; H, 3.46; N,
10.29. Found: C, 58.87; H, 3.33; N, 10.34.
4.1.6.13.
6-(5-Bromo-2-methoxyphenyl)-3-(4-ethyl-
phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid
(17i). Yield: 395 mg (44%, method C) of yellow crystals,
4.1.6.6. 6-(4-Chlorophenyl)-3-phenyl-1H-pyrazolo-
[3,4-b]pyridine-4-carboxylic acid (17b). Yields: 310 mg
(44%, method C) and 200 mg (44%, method D) of yellow
crystals, mp>300 ꢀC. IR (KBr): 3264, 1712, 1596. 1H
NMR (DMSO-d6) d 7.37–8.33 (m, 9H, ArH), 8.00 (s, 1H,
5-H), 13.49 (br s, 1H, COOH), 14.16 (br s, 1H, NH). 13C
NMR (DMSO-d6) d 107.8, 113.7, 128.6, 128.61, 129.1,
129.2, 129.66, 129.69, 134.51, 135.44, 137.45, 137.62,
154.37, 155.19, 168.04. Anal. Calcd for C19H12ClN3O2: C,
65.24; H, 3.46; N, 12.01. Found: C, 65.18; H, 3.58; N, 12.05.
mp>300 ꢀC. 1H NMR (DMSO-d6)
d 1.22 (t, 3H,
CH2CH3), 2.66 (q, 2H, CH2CH3), 3.86 (s, 3H, OCH3),
7.3–8.2 (m, 8H, ArH), 7.86 (s, 1H, 5-H), 13.5 (br s, 1H,
COOH), 14.09 (br s, 1H, NH). Anal. Calcd for
C22H18BrN3O3: C, 58.42; H, 4.01; N, 9.29. Found: C,
58.46; H, 4.11; N, 9.26.
4.1.7. General procedure for the synthesis of 1,6-diaryl-3-
methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids
16a–d. A mixture of 5-amino-3-methyl-1-phenylpyrazole
2 (1.1 mmol), pyruvic acid 13 (1.1 mmol) and the appropri-
ate aromatic aldehyde 14 (1.1 mmol) in 0.5 mL of DMF was
refluxed for 20–25 min. Then 5 mL of MeOH was added and
the reaction mixture was allowed to stand overnight. The
solid precipitated was removed by filtration, washed with
MeOH and air dried. If required, the crude compounds
were recrystallized from EtOH.
4.1.6.7. 6-(4-Methoxyphenyl)-3-phenyl-1H-pyrazolo-
[3,4-b]pyridine-4-carboxylic acid (17c). Yields: 290 mg
(42%, method C) and 190 mg (42%, method D) of yellow
crystals, mp>300 ꢀC. IR (KBr): 3260, 1708, 1596. 1H
NMR (DMSO-d6) d 7.0–8.30 (m, 9H, ArH), 7.91 (s, 1H,
5-H), 13.58 (br s, 1H, COOH), 14.02 (br s, 1H, NH), 3.83
(s, 3H, OCH3). Anal. Calcd for C20H15N3O3: C, 69.56; H,
4.38; N, 12.76. Found: C, 69.51; H, 4.25; N, 12.68.
4.1.7.1. 3-Methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]-
pyridine-4-carboxylic acid (16a). Yield: 140 mg (38%) of
yellow crystals, mp 285–287 ꢀC. 1H NMR (DMSO-d6)
d 2.70 (s, 3H, CH3), 7.3–8.4 (m, 10H, ArH), 8.15 (s, 1H,
5-H), 13.70 (br s, 1H, COOH). 13C NMR (DMSO-d6)
d 13.5, 114.3, 118.3, 121.1, 126.6, 127.1, 129.0, 129.1,
130.3, 133.3, 134.7, 138.5, 142.7, 150.7, 155.4, 170.1.
Anal. Calcd for C20H15N3O2: C, 72.94; H, 4.59; N, 12.76.
Found: C, 73.03; H, 4.41; N, 12.79.
4.1.6.8.
3-Phenyl-6-p-tolyl-1H-pyrazolo[3,4-b]pyr-
idine-4-carboxylic acid (17d). Yields: 260 mg (39%,
method C) and 180 mg (42%, method D) of yellow crystals,
mp>300 ꢀC. 1H NMR (DMSO-d6) d 7.3–8.2 (m, 9H, ArH),
7.94 (s, 1H, 5-H), 13.65 (br s, 1H, COOH), 14.08 (br s, 1H,
NH), 2.38 (s, 3H, CH3). Anal. Calcd for C20H15N3O2: C,
72.94; H, 4.59; N, 12.76. Found: C, 72.90; H, 4.67; N, 12.79.
4.1.6.9.
3-(4-Bromophenyl)-6-phenyl-1H-pyrazolo-
4.1.7.2. 6-(4-Chlorophenyl)-3-methyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-4-carboxylic acid (16b). Yield:
180 mg (44%) of yellow crystals, mp 280–282 ꢀC. 1H NMR
(DMSO-d6) d 2.68 (s, 3H, CH3), 7.3–8.4 (m, 9H, ArH),
8.14 (s, 1H, 5-H). Anal. Calcd for C20H14ClN3O2: C, 66.03;
H, 3.88; N, 11.55. Found: C, 66.07; H, 3.72; N, 11.57.
[3,4-b]pyridine-4-carboxylic acid (17e). Yield: 310 mg
(40%, method C) of yellow crystals, mp>300 ꢀC. 1H
NMR (DMSO-d6) d 7.5–8.2 (m, 9H, ArH), 8.00 (s, 1H,
5-H), 14.20 (br s, 1H, NH). Anal. Calcd for C19H12BrN3O2:
C, 57.89; H, 3.07; N, 10.66. Found: C, 57.84; H, 3.15; N,
10.61.
4.1.7.3. 6-(4-Methoxyphenyl)-3-methyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-4-carboxylic acid (16c). Yield:
170 mg (42%) of yellow crystals, mp 278–280 ꢀC. 1H
NMR (DMSO-d6) d 2.68 (s, 3H, CH3), 3.84 (s, 3H,
OCH3), 7.1–8.35 (m, 9H, ArH), 8.09 (s, 1H, 5-H), 14.1 (br
s, 1H, COOH). Anal. Calcd for C21H17N3O3: C, 70.18; H,
4.77; N, 11.69. Found: C, 70.22; H, 4.58; N, 11.72.
4.1.6.10. 3-(4-Bromophenyl)-6-(4-chlorophenyl)-1H-
pyrazolo[3,4-b]pyridine-4-carboxylic acid (17f). Yield:
380 mg (45%, method C) of yellow crystals, mp>300 ꢀC.
1H NMR (DMSO-d6) d 7.5–8.3 (m, 8H, ArH), 8.02 (s, 1H,
5-H), 13.4 (br s, 1H, COOH), 14.24 (br s, 1H, NH). Anal.
Calcd for C19H11BrClN3O2: C, 53.24; H, 2.59; N, 9.80.
Found: C, 53.20; H, 2.50; N, 9.84.
4.1.7.4. 3-Methyl-1-phenyl-6-p-tolyl-1H-pyrazolo[3,4-
b]pyridine-4-carboxylic acid (16d). Yield: 140 mg (36%)
4.1.6.11. 3-(4-Bromophenyl)-6-(4-methoxyphenyl)-1H-
pyrazolo[3,4-b]pyridine-4-carboxylic acid (17g). Yield:
350 mg (42%, method C) of yellow crystals, mp>300 ꢀC.
1H NMR (DMSO-d6) d 7.0–8.30 (m, 8H, ArH), 7.95 (s, 1H,
5-H), 14.12 (br s, 1H, NH), 3.83 (s, 3H, OCH3). Anal. Calcd
for C20H14BrN3O3: C, 56.62; H, 3.33; N, 9.90. Found: C,
56.58; H, 3.23; N, 9.94.
1
of yellow crystals, mp 275–277 ꢀC. H NMR (DMSO-d6)
d 2.68 (s, 3H, CH3), 2.38 (s, 3H, CH3), 7.25–8.25 (m, 9H,
ArH), 8.11 (s, 1H, 5-H). Anal. Calcd for C21H17N3O2: C,
73.45; H, 4.99; N, 12.24. Found: C, 73.48; H, 4.82; N, 12.21.
4.1.8. General procedures for the synthesis of ethyl
6-aryl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxyl-
ates 20c–h and ethyl 3,6-diaryl-1H-pyrazolo[3,4-b]-
pyridine-4-carboxylates 21c–h. Conventional method
E: A mixture of corresponding 5-aminopyrazol 1 or 3a
(1.3 mmol), ethyl pyruvate 19 (1.3 mmol) and the appropri-
ate aromatic aldehyde 14 (1.3 mmol) in 5 mL of acetic acid
4.1.6.12. 3-(4-Bromophenyl)-6-p-tolyl-1H-pyrazolo-
[3,4-b]pyridine-4-carboxylic acid (17h). Yield: 370 mg
1
(46%, method C) of yellow crystals, mp>300 ꢀC. H NMR
(DMSO-d6) d 7.3–8.2 (m, 8H, ArH), 7.96 (s, 1H, 5-H), 13.6
(br s, 1H, COOH), 14.12 (br s, 1H, NH), 2.38 (s, 3H, CH3).

1240
V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
was refluxed for 100–120 min (TLC control). Then 10 mL of
EtOH/H2O (1:1) was added to the reaction mixture, the crys-
tals formed were removed by filtration, washed with EtOH/
H2O (1:1) and air dried. The crude products were recrystal-
lized from EtOH.
(%)¼362 (100%) [M+]. Anal. Calcd for C16H14BrN3O2: C,
53.35; H, 3.92; N, 11.67. Found: C, 53.21; H, 4.06; N, 11.63.
4.1.8.5. Ethyl 6-(3-chlorophenyl)-3-methyl-1H-pyr-
azolo[3,4-b]pyridine-4-carboxylate (20g). Yield: 160 mg
(40%, method F) of yellowish crystals, mp 112–114 ꢀC.
1H NMR (DMSO-d6) d 1.39 (t, J¼7.0 Hz, 3H, CH3CH2),
2.57 (s, 3H, CH3), 4.44 (q, J¼7.0 Hz, 2H, CH3CH2), 7.53
(d, J¼4.6 Hz, 2H, ArH), 8.00 (s, 1H, 5-H), 8.07 (dd, J¼
4.6, 1.5 Hz, 1H, ArH), 8.15 (d, J¼1.5 Hz, 1H, ArH), 13.66
(s, 1H, NH). 13C NMR (DMSO-d6) d 14.5, 16.1, 62.4,
109.7, 114.1, 126.2, 127.2, 130.0, 131.3, 134.3, 134.4,
140.4, 154.1, 165.7. MS (El, 70 eV): m/z (%)¼316 (100%)
[M+]. Anal. Calcd for C16H14ClN3O2: C, 60.86; H, 4.47;
N, 13.31. Found: C, 60.71; H, 4.54; N, 13.28.
MW-assisted method F: A mixture of the corresponding
5-aminopyrazole 1 or 3a (1.3 mmol), ethyl pyruvate 19
(1.3 mmol) and the appropriate aromatic aldehyde 14
(1.3 mmol) in 1 mL of EtOH containing one drop of concd
HCl was irradiated under sealed vessel microwave condi-
tions at 150 ꢀC for 10 min in a 5 mL microwave process
vial. Then 4 mL of EtOH/H2O (1:1) was added to the reac-
tion mixture, the crystals formed were removed by filtration,
washed with EtOH/H2O (1:1) and air dried.
4.1.8.1. Ethyl 6-(4-methoxyphenyl)-3-methyl-1H-pyr-
azolo[3,4-b]pyridine-4-carboxylate (20c). Yields: 100 mg
(25%, method E) and 170 mg (42%, method F) of yellowish
4.1.8.6. Ethyl 6-(2-chlorophenyl)-3-methyl-1H-pyr-
azolo[3,4-b]pyridine-4-carboxylate (20h). Yield: 140 mg
(35%, method F) of yellowish crystals, mp 170 ꢀC (dec).
1H NMR (DMSO-d6) d 1.37 (t, J¼7.0 Hz, 3H, CH3CH2),
2.64 (s, 3H, CH3), 4.44 (q, J¼7.0 Hz, 2H, CH3CH2), 7.4–
7.7 (m, 4H, ArH), 7.73 (s, 1H, 5-H), 13.75 (s, 1H, NH).
13C NMR (DMSO-d6) d 14.5, 16.3, 62.4, 109.2, 118.0,
128.0, 130.5, 131.1, 131.7, 132.2, 133.2, 138.6, 141.2,
154.0, 155.8, 165.5. MS (El, 70 eV): m/z (%)¼316 (100%)
[M+]. Anal. Calcd for C16H14ClN3O2: C, 60.86; H, 4.47;
N, 13.31. Found: C, 60.99; H, 4.57; N, 13.28.
1
crystals, mp 177–180 ꢀC. H NMR (DMSO-d6) d 1.41 (t,
J¼7.0 Hz, 3H, CH3CH2), 2.58 (s, 3H, CH3), 3.83 (s, 3H,
CH3O), 4.45 (q, J¼7.0 Hz, 2H, CH3CH2), 7.07 (d, J¼
9 Hz, 2H, ArH), 7.97 (s, 1H, 5-H), 8.12 (d, J¼9 Hz, 2H,
ArH), 13.54 (s, 1H, NH). 13C NMR (DMSO-d6) d 14.5,
16.2, 55.8, 62.2, 108.8, 113.5, 114.8, 129.0, 130.8, 134.0,
141.0, 154.4, 155.6, 161.2, 165.9. MS (El, 70 eV): m/z
(%)¼312 (100%) [M+]. Anal. Calcd for C17H17N3O3: C,
65.58; H, 5.50; N, 13.50. Found: C, 65.40; H, 5.59; N, 13.48.
4.1.8.7. Ethyl 6-(4-methoxyphenyl)-3-phenyl-1H-pyr-
azolo[3,4-b]pyridine-4-carboxylate (21c). Yields: 100 mg
(21%, method E) and 210 mg (43%, method F) of yellowish
4.1.8.2. Ethyl 3-methyl-6-p-tolyl-1H-pyrazolo[3,4-
b]pyridine-4-carboxylate (20d). Yields: 80 mg (20%,
method E) and 140 mg (42%, method F) of yellowish crystals,
mp 188–191 ꢀC. 1H NMR (DMSO-d6) d 1.38 (t, J¼
7.0 Hz, 3H, CH3CH2), 2.34 (s, 3H, CH3), 2.57 (s, 3H,
CH3O), 4.43 (q, J¼7.0 Hz, 2H, CH3CH2), 7.30 (d, J¼
8.3 Hz, 2H, ArH), 7.96 (s, 1H, 5-H), 8.02 (d, J¼8.3 Hz, 2H,
ArH), 13.58 (s, 1H, NH). 13C NMR (DMSO-d6) d 14.5,
21.2, 62.21, 109.1, 113.8, 127.4, 130.0, 134.0, 135.6, 140.0,
141.0, 154.4, 155.8, 165.8. MS (El, 70 eV): m/z (%)¼296
(100%) [M+]. Anal. Calcd for C17H17N3O2: C, 69.14; H,
5.80; N, 14.23. Found: C, 69.25; H, 5.71; N, 14.26.
1
crystals, mp 128–130 ꢀC. H NMR (DMSO-d6) d 0.75 (t,
J¼7.0 Hz, 3H, CH3CH2), 3.84 (s, 3H, CH3O), 3.93 (q,
J¼7.0 Hz, 2H, CH3CH2), 7.1–8.2 (m, 9H, ArH), 7.97 (s,
1H, 5-H), 14.18 (s, 1H, NH). 13C NMR (DMSO-d6)
d 13.5, 55.8, 62.0, 107.1, 113.6, 114.8, 128.5, 128.6,
128.7, 129.2, 130.6, 134.7, 135.3, 144.6, 154.2, 156.1,
161.4, 166.7. MS (El, 70 eV): m/z (%)¼374 (100%) [M+].
Anal. Calcd for C22H19N3O3: C, 70.76; H, 5.13; N, 11.25.
Found: C, 70.60; H, 5.25; N, 11.27.
4.1.8.8. Ethyl 3-phenyl-6-p-tolyl-1H-pyrazolo[3,4-
b]pyridine-4-carboxylate (21d). Yields: 85 mg (18%,
method E) and 220 mg (48%, method F) of yellowish crys-
4.1.8.3. Ethyl 6-(4-fluorophenyl)-3-methyl-1H-pyr-
azolo[3,4-b]pyridine-4-carboxylate (20e). Yields: 90 mg
(23%, method E) and 180 mg (47%, method F) of yellowish
1
tals, mp 188–191 ꢀC. H NMR (DMSO-d6) d 0.75 (t, J¼
1
crystals, mp 160–163 ꢀC. H NMR (DMSO-d6) d 1.39 (t,
7.0 Hz, 3H, CH3CH2), 2.37 (s, 3H, CH3), 3.91 (q, J¼
7.0 Hz, 2H, CH3CH2), 7.3–8.2 (m, 9H, ArH), 7.99 (s, 1H,
5-H), 14.20 (s, 1H, NH). 13C NMR (DMSO-d6) d 13.5,
21.3, 62.1, 107.4, 113.2, 127.6, 128.5, 128.6, 128.8, 130.1,
134.7, 135.4, 135.5, 140.2, 144.6, 154.2, 156.4, 166.6. MS
(El, 70 eV): m/z (%)¼358 (100%) [M+]. Anal. Calcd for
C22H19N3O2: C, 73.93; H, 5.36; N, 11.76. Found: C,
74.09; H, 5.22; N, 11.79.
J¼7.0 Hz, 3H, CH3CH2), 2.57 (s, 3H, CH3), 4.43 (q, J¼
7.0 Hz, 2H, CH3CH2), 7.33 (m, 2H, ArH), 7.97 (s, 1H,
5-H), 8.17 (m, 2H, ArH), 13.61 (s, 1H, NH). 13C NMR
(DMSO-d6) d 14.5, 16.2, 62.3, 109.2, 113.9, 116.1, 116.4,
129.7, 129.9, 134.2, 134.8, 141.0, 145.3, 154.7, 162.3,
165.1, 165.7. Anal. Calcd for C16H14FN3O2: C, 64.21; H,
4.71; N, 14.04. Found: C, 64.14; H, 4.87; N, 14.02.
4.1.8.4. Ethyl 6-(4-bromophenyl)-3-methyl-1H-pyr-
azolo[3,4-b]pyridine-4-carboxylate (20f). Yield: 210 mg
4.1.8.9. Ethyl 6-(4-fluorophenyl)-3-phenyl-1H-pyr-
azolo[3,4-b]pyridine-4-carboxylate (21e). Yields: 100 mg
(22%, method E) and 225 mg (48%, method F) of yellowish
1
(45%, method F) of yellowish crystals, mp 131–135 ꢀC. H
1
NMR (DMSO-d6) d 1.39 (t, J¼7.0 Hz, 3H, CH3CH2), 2.58
(s, 3H, CH3), 4.44 (q, J¼7.0 Hz, 2H, CH3CH2), 7.70 (d,
J¼8.8 Hz, 2H, ArH), 7.99 (s, 1H, 5-H), 8.08 (d, J¼
8.8 Hz, 2H, ArH), 13.66 (s, 1H, NH). 13C NMR (DMSO-d6)
d 14.5, 16.2, 62.3, 109.5, 113.9, 123.9, 129.6, 132.4, 134.3,
137.5, 141.0, 154.3, 154.5, 166.0. MS (El, 70 eV): m/z
crystals, mp 160–163 ꢀC. H NMR (DMSO-d6) d 0.75 (t,
J¼7.0 Hz, 3H, CH3CH2), 3.93 (q, J¼7.0 Hz, 2H,
CH3CH2), 7.3–8.3 (m, 9H, ArH), 8.03 (s, 1H, 5-H), 14.22
(s, 1H, NH). 13C NMR (DMSO-d6) d 13.5, 62.1, 107.6,
114.0, 116.3, 116.5, 128.5, 128.7, 128.8, 130.0, 130.1,
134.8, 135.6, 154.1, 150.2, 155.3, 166.5. MS (El, 70 eV):

V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
1241
m/z (%)¼362 (100%) [M+]. Anal. Calcd for C22H19N3O2: C,
References and notes
73.93; H, 5.36; N, 11.76. Found: C, 74.09; H, 5.22; N, 11.79.
1. (a) Chebanov, V. A.; Desenko, S. M. Curr. Org. Chem. 2006,
10, 297; (b) Desenko, S. M. Chem. Heterocycl. Compd.
(Engl. Transl.) 1995, 31, 125; (c) Desenko, S. M.; Orlov,
V. D. Azaheterocycles Based on Aromatic Unsaturated
Ketones; Folio: Kharkov, 1998; pp 38–101.
4.1.8.10. Ethyl 6-(4-bromophenyl)-3-phenyl-1H-pyr-
azolo[3,4-b]pyridine-4-carboxylate (21f). Yield: 240 mg
(45%, method F) of yellowish crystals, mp 131–135 ꢀC.
1H NMR (DMSO-d6) d 0.75 (t, J¼7.0 Hz, 3H, CH3CH2),
3.94 (q, J¼7.0 Hz, 2H, CH3CH2), 7.4–8.3 (m, 9H, ArH),
8.04 (s, 1H, 5-H), 14.20 (s, 1H, NH). MS (El, 70 eV): m/z
(%)¼422 (100%) [M+]. Anal. Calcd for C21H16BrN3O2: C,
59.73; H, 3.82; N, 9.95. Found: C, 59.60; H, 3.99; N, 10.00.
2. (a) Lipson, V. V.; Desenko, S. M.; Shirobokova, M. G.;
Borodina, V. V. Chem. Heterocycl. Compd. (Engl. Transl.)
2003, 39, 1213; (b) Chebanov, V. A.; Desenko, S. M.;
Sakhno, Y. I.; Panchenko, E. S.; Saraev, V. E.; Musatov, V. I.;
Konev, V. F. Fiziol. Akt. Rechovini 2002, 33, 10; (c)
Chebanov, V. A.; Sakhno, Y. I.; Desenko, S. M.; Shishkina,
S. V.; Musatov, V. I.; Shishkin, O. V.; Knyazeva, I. V. Synthesis
2005, 2597; (d) Lipson, V. V.; Desenko, S. M.; Borodina, V. V.;
Shirobokova, M. G.; Musatov, V. I. Russ. J. Org. Chem. 2005,
41, 114; (e) Lipson, V. V.; Desenko, S. M.; Shishkina, S. V.;
Shirobokova, M. G.; Shishkin, O. V.; Orlov, V. D. Chem.
Heterocycl. Compd. (Engl. Transl.) 2003, 39, 1041; (f) Lipson,
V. V.; Borodina, V. V.; Shirobokova, M. G.; Karnozhitskaya,
T. M. Fiziol. Akt. Rechovini 2002, 2, 10.
4.1.8.11. Ethyl 6-(3-chlorophenyl)-3-phenyl-1H-pyr-
azolo[3,4-b]pyridine-4-carboxylate (21g). Yield: 200 mg
(41%, method F) of yellowish crystals, mp 173–175 ꢀC.
1H NMR (DMSO-d6) d 0.75 (t, J¼7.0 Hz, 3H, CH3CH2),
3.94 (q, J¼7.0 Hz, 2H, CH3CH2), 7.4–8.4 (m, 9H, ArH),
8.09 (s, 1H, 5-H), 14.18 (s, 1H, NH). MS (El, 70 eV): m/z
(%)¼378 (100%) [M+]. Anal. Calcd for C21H16ClN3O2: C,
66.76; H, 4.27; N, 11.12. Found: C, 66.89; H, 4.15; N, 11.14.
4.1.8.12. Ethyl 6-(2-chlorophenyl)-3-phenyl-1H-pyr-
azolo[3,4-b]pyridine-4-carboxylate (21h). Yield: 180 mg
(36%, method F) of yellowish crystals, mp 120–123 ꢀC.
1H NMR (DMSO-d6) d 0.73 (t, J¼7.0 Hz, 3H, CH3CH2),
3.91 (q, J¼7.0 Hz, 2H, CH3CH2), 7.4–7.8 (m, 9H, ArH),
7.69 (s, 1H, 5-H), 14.15 (s, 1H, NH). Anal. Calcd for
C21H16ClN3O2: C, 66.76; H, 4.27; N, 11.12. Found: C,
66.60; H, 4.37; N, 11.09.
3. (a) Desenko, S. M.; Orlov, V. D.; Getmanskii, N. V.; Shishkin,
O. V.; Lindeman, S. V.; Struchkov, Yu. T. Chem. Heterocycl.
Compd. (Engl. Transl.) 1993, 29, 406; (b) Wermann, K.;
Hartman, M. Synthesis 1991, 189; (c) Desenko, S. M.; Orlov,
V. D.; Getmanskii, N. V.; Shishkin, O. V.; Lindeman, S. V.;
Struchkov, Yu. T. Dokl. Akad. Nauk 1992, 324, 801; (d)
Desenko, S. M.; Orlov, V. D.; Estrada, Kh. Chem. Heterocycl.
Compd. (Engl. Transl.) 1990, 26, 839; (e) Desenko, S. M.;
Orlov, V. D.; Estrada, Kh.; Ivkov, S. M. Chem. Heterocycl.
Compd. (Engl. Transl.) 1991, 27, 555.
4.2. X-ray diffraction data
4. See, for example: (a) Kozminykh, V. O.; Kozminykh, E. M.
Selected Methods for Synthesis and Modification of Hetero-
cycles; Kartsev, V. G., Ed.; IBS: Moscow, 2002; pp 263–279;
(b) Saloutin, V. I.; Burgart, Ya. V.; Chupakhin, O. N. Usp.
Khim. 1999, 68, 227; (c) Perevalov, S. G.; Burgart, Ya. V.;
Saloutin, V. I.; Chupakhin, O. N. Usp. Khim. 2001, 70, 1039;
(d) Nosek, E. Collect. Czech. Chem. Commun. 1950, 15, 335;
(e) Mueller, R. J. Prakt. Chem. 1959, 132; (f) Armand, J.;
Armand, Y.; Boulares, L.; Bellec, C.; Pinson, J. J. Heterocycl.
Chem. 1985, 22, 1519; (g) Kruglenko, V. P.; Klyuev, N. A.;
Povstyanoi, M. V.; Timoshin, A. A. Chem. Heterocycl.
Compd. 1998, 34, 232; (h) Berezina, E. S.; Koz’minykh,
V. O.; Igidov, N. M.; Shirinkina, S. S.; Koz’minykh, E. N.;
Makhmudov, R. R.; Bukanova, E. V. Russ. J. Org. Chem.
2001, 37, 539; (i) Kistanova, N. S.; Mashevskaya, I. V.;
Bozdyreva, K. S.; Maslivets, A. N. Chem. Heterocycl.
Compd. 2003, 39, 673.
5. (a) Abdel-Haby, S. A. L.; Badawy, M. A.; Kadry, A. M.;
Mosselhi, M. A. N. J. Heterocycl. Chem. 1987, 24, 1587; (b)
Abdel-Megid, M. Pharmazie 2000, 55, 263; (c) El-Maati,
T. M. A. Boll. Chim. Farm 1999, 138, 272.
6. (a) Epling, G. A.; Provatas, A. A. Chem. Commun. 2002,
1036; (b) Garzarolli-Thurnlackh, K. Monatsh. Chem. 1899,
20, 487; (c) Jablonski, W. Ber. Dtsch. Chem. Ges. 1900,
33, 2925.
The crystals of C22H18N3O3Br are monoclinic. At 293 K
ꢀ
˚
a¼7.622(2), b¼16.991(6), c¼15.354(6) A, b¼95.92(3) ,
V¼1978(1) A , space group P21/c, Z¼4, dcalc¼1.519 g/cm3,
3
˚
m¼2.108 mmꢁ1, F(000)¼920. Intensity of 3657 reflections
(3392 independent, Rint¼0.055) was measured on an auto-
matic four circles Siemens P3/PC diffractometer (graphite
monochromated Mo Ka radiation, Q/2Q scanning, 2Qmax
¼
50ꢀ). The absorption correction was performed analytically
(Tmin¼0.365, Tmax¼0.678). The structure was solved by di-
rect method using SHELX97 package.15 The positions of
hydrogen atoms were located from the electron density
difference maps and refined by the ‘riding’ model with
Uiso¼nUeq of non-hydrogen atoms bonded to given hydro-
gen atoms (n¼1.5 for methyl and hydroxyl groups and
n¼1.2 for other hydrogen atoms). Full-matrix least-squares
refinement against F2 in the anisotropic approximation using
3355 reflections converged to R1¼0.061 (for 1865 reflec-
tions with F>4s(F)), wR2¼0.130, S¼0.991. Atomic coordi-
nates and crystallographic parameters have been deposited
to the Cambridge Crystallographic Data Centre, deposition
number CCDC 617647. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44 1223 336 033, e-mail:
deposit@ccdc.cam.ac.uk).
7. Borsche, W. Ber. Dtsch. Chem. Ges. 1908, 41, 3886.
8. See, for example: (a) Alajarin, R.; Avarez-Buila, J.; Vaquero,
J. J.; Sunkel, C.; Fau, J.; Statkov, P.; Sanz, J. Tetrahedron:
Asymmetry 1993, 4, 617; (b) Bossert, F.; Vater, W. Med. Res.
Rev. 1989, 9, 291; (c) Trigle, D. J.; Langs, D. A.; Janis,
R. A. Med. Res. Rev. 1989, 9, 123; (d) Tsuda, Y.; Mishina,
Acknowledgements
The present work was supported by an INTAS grant (Ref. no.
04-83-2844). We thank Biotage AG for the use of Emrys
Creator EXP and Initiator 8 microwave reactors.

1242
V. A. Chebanov et al. / Tetrahedron 63 (2007) 1229–1242
T.; Obata, M.; Araki, K.; Inui, J.; Nakamura, T., Patent
12. (a) Xu, Y.; Guo, Q.-X. Heterocycles 2004, 63, 903; (b) Hamelin,
J.; Bazureau, J.-P.; Texier-Boullet, F. Microwaves in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002;
pp 253–294; (c) Besson, T.; Brain, C. T. Microwave Assisted
8,504,172 PCT Int., 1985; Chem. Abstr. 104, 207298; (e)
Tsuda, Y.; Mishina, T.; Obata, M.; Araki, K.; Inui, J.;
Nakamura, T. Patent 61,227,584 Jpn., 1986; Chem. Abstr.
109, 120988; (f) Tsuda, Y.; Mishina, T.; Obata, M.; Araki,
K.; Inui, J.; Nakamura, T. 19,870,408 Eur. Pat., 1987; Chem.
Abstr. 106, 213976; (g) Atwal, K. S.; Vaccaro, W.; Lloyd, J.;
Finlay, H.; Yan, L.; Bhandaru, R. S. 20,010,607 PCT Int.,
2001; Chem. Abstr. 135, 19660; (h) Atwal, K. S.; Moreland,
S. Bioorg. Med. Chem. Lett. 1991, 1, 291.
€
Organic Synthesis; Lidsrom, P., Tieney, J. P., Eds.; Blackwell:
Oxford, 2005; (d) Stadler, A.; Kappe, C. O. J. Comb. Chem.
2001, 3, 624; (e) Kappe, C. O.; Stadler, A. Combinatorial
Chemistry, Part B; Bunin, B. B., Morales, G., Eds.; Elsevier
¨
Science: 2003; pp 197–223; (f) Ohberg, L.; Westman, J.
Synlett 2001, 1296; (g) Bagley, M. C.; Singh, N. Synlett 2002,
1718; (h) Wilson, N. S.; Sarko, C. R.; Roth, G. P. Tetrahedron
Lett. 2002, 43, 581; (i) Devi, I.; Bhuyan, P. J. Tetrahedron
9. Annan, N.; Paris, R.; Jordan, F. J. Am. Chem. Soc. 1999, 111,
8895.
ꢀ
Lett. 2004, 45, 8625; (j) Mont, N.; Teixido, J.; Borell, J. I.;
Kappe, C. O. Tetrahedron Lett. 2003, 44, 5385; (k) Mont, N.;
10. (a) Hartmann, H.; Liebscher, J. Synthesis 1984, 276; (b)
Nenaidenko, V. G.; Golubinskii, I. V.; Lenkova, O. N.;
Shastin, A. V.; Balenkova, E. S. Russ. J. Org. Chem. 2004,
40, 1518; (c) Hennig, L.; Hofmann, J.; Alva-Astudillo, M.;
Mann, G. J. Prakt. Chem. 1990, 332, 351.
11. (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250; (b)
Hayes, B. L. Aldrichimica Acta 2004, 37, 66; (c) Larhed, M.;
Hallberg, A. Drug Discov. Today 2001, 6, 406; Wathey, B.;
ꢀ
Teixido, J.; Borell, J. I.; Kappe, C. O. Mol. Diversity 2003, 7,
ꢀ
ꢀ
153; (l) Mont, N.; Fernandez_Megido, L.; Teixido, J.; Kappe,
C. O.; Borell, J. I. QSAR Comb. Sci. 2004, 23, 836; (m) Tye,
H.; Whittaker, M. Org. Biomol. Chem. 2004, 2, 813; (n)
Molteni, V.; Hamilton, M. M.; Mao, L.; Crane, C. M.;
Termin, A. P.; Wilson, D. M. Synthesis 2002, 1669; (o)
Ireland, S. M.; Tye, H.; Whittaker, M. Tetrahedron Lett. 2003,
44, 4369.
€
Tierney, J.; Lidstrom, P.; Westman, J. Drug Discov. Today
2002, 7, 373; (d) Al-Obeidi, F.; Austin, R. E.; Okonya, J. F.;
Bond, D. R. S. Mini-Rev. Med. Chem. 2003, 3, 449; (e)
Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Discov. 2006, 5,
51; (f) Shipe, W. D.; Wolkenberg, S. E.; Lindsley, C. W.
Drug Discov. Today Technol. 2005, 2, 155; (g) Kappe, C. O.;
Stadler, A. Microwaves in Organic and Medicinal Chemistry;
Wiley-VCH: Weinheim, 2005.
13. Burgi, H.-B.; Dunitz, J. D. Structure Correlation; VCH:
Weinheim, 1994; Vol. 2, p 741.
14. Zefirov, Yu. V.; Zorky, P. M. Usp. Khim. 1989, 58, 713.
15. Sheldrick, G. M. SHELXTL PLUS. PC Version. A system of
computer programs for the determination of crystal structure
from X-ray diffraction data. Rev. 5.1, 1998.