Transformation of 4-oxo-4H-[1]-benzopyran-3-carboxaldehydes into pyrazolo[3,4-b]pyridines

Article abstract of DOI:10.1002/jhet.5570430405

Reaction of 6-methyl-4-oxo-4H-[1]-benzopyran-3-carboxaldehyde 1 with 5-amino-3-methyl-1-phenyl-pyrazole 2 in alcoholic reaction media in the presence of 4-toluenesulfonic acid as catalyst afforded 5-(2-hydroxy-5-methylbenzoyl)-3- methyl-1-phenyl-1H-pyrazo

Full text of DOI:10.1002/jhet.5570430405

Jul-Aug 2006
843
Transformation of 4-Oxo-4H-[1]-benzopyran-3-carboxaldehydes into
Pyrazolo[3,4-b]pyridines
*
Henrieta Stankoviꢀová and Anton Gáplovskꢁ
Institute of Chemistry, Faculty of Natural Sciences, Comenius University, Mlynská dolina CH-2, 842 15
Bratislava, Slovak Republic, stankovh@fns.uniba.sk
Margita Lácová and Jarmila Chovancová
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University, Mlynská dolina CH-2, 842
1
5 Bratislava, Slovak Republic
Agnieszka Puchaꢂa
Institute of Chemistry, Swietokrzyska University, Checinska 5, 25-020 Kielce, Poland
Received July 22, 2005
O
N
Ph
R
CHO
O
HN
N
N
N
R
R
Ph
O
O
HN
+
R
O
O
OCH3
NH
2
CH(OCH
3 2
)
OH
N
Ph
N
N
N
OH
N
Ph
Reaction of 6-methyl-4-oxo-4H-[1]-benzopyran-3-carboxaldehyde 1 with 5-amino-3-methyl-1-phenyl-
pyrazole 2 in alcoholic reaction media in the presence of 4-toluenesulfonic acid as catalyst afforded 5-(2-
hydroxy-5-methylbenzoyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine 3 and 2-methoxy-6-methyl-3-
(3-methyl-1-phenylpyrazol-5-ylaminomethylene)chroman-4-one 7. We explain the mechanism of
formation of both products on the basis of kinetic study of individual reaction steps.
J. Heterocyclic Chem., 43, 843 (2006).
Introduction.
philes [13]. We now report a kinetic investigation of
reaction between 6-methyl-4-oxo-4H-[1]-benzopyran-3-
Important role of 6-substituted-4-oxo-4H-[1]-benzopyran-
-carboxaldehydes (3-formylchromones) 1 as versatile
carboxaldehyde 1 (R = CH ) with 5-amino-3-methyl-1-
3
3
phenylpyrazole 2. 5-Aminopyrazoles are useful reactive
agents for synthesis of pyrazolo[3,4-b]pyridines under
highly acidic annelation conditions. An electrophilic
attack at the C-4 position of pyrazole ring takes place in
the presence of suitable reaction counterpart [14]. The aim
of this study was to contribute to clarification of exact
reaction mechanism of reaction of 1 with amines. The
choice of suitable nucleophile was not random. Primary
enamines as ambident nucleophiles can form upon
condensation with 1 a new ring system. The mechanisms
of these reactions are partially clarified, the probable
reaction courses were proposed [15,16].
synthons in heterocyclic chemistry is well known [1,2].
Although a lot of heterocycles have been prepared from 1,
the exact route of their formation is not always clear.
Formation of products is usually preceded by formation of
one or two intermediates, making the kinetics of these
reactions complicated. Aldehydes
potential sites for attack of nucleophile viz. C-2, CHO, C-
, the last one having obviously the least electrophilicity
1
contain three
4
compared to that at the two other centers. It is very
difficult to pintpoint whether an initial step of the reaction
is C-2 or CHO attack of the nucleophile because of
“chemical symmetry” of these reaction centers.
Results and Discussion.
Unfortunately none of the published methods for the
preparation of 3-formylchromones is suitable for
incorporation of the specific labeling [3-12].
Recently in our previous study we described the acid
catalyzed reaction of aldehydes 1 with weak N-nucleo-
Reaction of 6-methyl-4-oxo-4H-[1]-benzopyran-3-car-
boxaldehyde 1 with 5-amino-3-methyl-1-phenylpyrazole
2 afforded 5-(2-hydroxy-5-methylbenzoyl)-3-methyl-1-
phenyl-1H-pyrazolo[3,4-b]pyridine 3 (Scheme I). The

8
44
H. Stankoviꢀová, A. Gáplovskꢁ, M. Lácová, J. Chovancová, A. Puchaꢂa
Vol 43
reaction was carried out by refluxing equimolar amounts
of aldehyde 1 and pyrazole 2 in alcohol in the presence of
3,0
4
-toluenesulfonic acid as catalyst. The product is isolated
2
,5
in good yield (85%) as stable crystalline product and
easily purified by recrystallization from alcohol. Alcohols
as solvents were found most suitable for synthesis.
Dioxane, toluene or chloroform as solvents can also be
used but the reaction is slower and the yields of product
are lower with lower purity.
2,0
1,5
1,0
7
3
0,5
Scheme
I
1
Ph
N
2
N
0,0
270
360
450
O
HN
O
R
R
ꢀ[nm]
cat.
CHO
N
O
O
OH
N
OH
N
kin2
R
CHO
Ph
4
3
resp. Ph
N
N
Figure 1. UV-VIS spectra of compounds in methanol.
1
O
HN
cat. kin3
Ph
+
R
kin1
NH
2
CH(OCH
3
)
2
N
N
OH
N
Ph
O
HN
N
5
Ph
R
or
N
N
2
O
HN
O
OCH
3
R
7
CH(OCH
3
)(OH)
OH
6
Unlike 5-amino-3-methyl-1-phenylpyrazole, 5-amino-
3
-methyl-1H-pyrazole reacts with 3-formylchromones in
ethanol affording 6-(2-hydroxybenzoyl)pyrazolo[1,5-a]-
pyrimidines. No pyrazolo[3,4-b]pyridines were isolated in
that case [17]. Introduction of a substituent on the N-1
atom of pyrazole ring prevents formation of tautomers
and changes its reactivity towards 3-formylchromone.
Pyrazolo[3,4-b]pyridines were also obtained when reac-
tion of 1 with 2 was carried out in glacial acetic acid, but
with lower yield (46%) [15].
Figure 2a. Fluorescence emission spectra of compounds in dioxane.
1000
mixing 1+2
Reactivity of aldehyde 1 (R = CH ) and pyrazole 2
3
equilibrium kin1
equilibrium kin2
equilibrium kin1 + catalyst
as well as the number of reaction steps is dependent
on reaction conditions. On the basis of kinetic
experiments and results of synthesis we suggested
for formation of 5-(2-hydroxy-5-methylbenzoyl)-3-
methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine 3 a mech-
anism depicted in Scheme I.
750
500
250
The study of reaction kinetics was performed in
three different solvents: dioxane, methanol and 2-
propanol in the presence of 4-toluenesulfonic acid as
catalyst or without catalyst. UV-VIS absorption
spectra were used for monitoring the kinetics of
above process. All of the components of the reaction
mixture had different absorption bands and
intensities (Figure 1). Fluorescence spectroscopy was
used with benefit for unambiguous identification of
reaction mixture components (Figure 2).
0
400
450
500
550
ꢀ[nm]
Figure 2b. Fluorescence emission spectra of reaction mixtures in
dioxane (ꢀex = 350 nm).
The first step of the reaction is a nucleophilic attack to
the 2-position of the chromone system followed by

Jul-Aug 2006
Transformation of 4-oxo-4H-[1]-benzopyran-3-carboxaldehydes
into pyrazolo[3,4-b]pyridines
845
benzopyrone ring opening. The isolation of intermediate 4
from reaction mixture was not successful. H NMR
from 5, resp. 6. Concentration of chroman-4-one 7 is
relatively low and approximately after 1200 s moderately
decreases. Pyrazolo[3,4-b]pyridine 3 is formed from
compound 7 by rate comparable with that of formation of
7 from 5, resp. 6. Absorption spectra of 7 are overlapping
with spectra of intermediates 5, resp. 6 and partially with
spectra of starting aldehyde (Figure 5b).
1
spectroscopy was used to prove its formation. Spectra
were recorded immediately after mixing equimolar
amounts of starting compounds 1 and 2 in suitable
solvent, they revealed a signal at ꢀ 5.58 due to phenolic
OH group, dublet at ꢀ 7.62 for CH group and signal at ꢀ
9
.76 for aldehydic group. Formation of intermediate is
expressed in UV-VIS spectra as an appearance of
absorption band at ꢁ = 340 nm (Figure 3). Increase of
absorbance at 340 nm was observed predominantly in
reaction mixtures without catalyst in protic solvents.
Intermediate 5, respectively 6 is formed relatively fast in
methanol. Its formation is observable in UV-VIS spectra
few seconds after mixing starting materials.
Figure 4. Time change of absorbance due to formation of 3 in dioxane.
Figure 3. UV-VIS spectra of equilibrium states kin1 in various solvents
and of aldehyde.
Insignificant increase of absorbance (at 340 nm
corresponding to absorbance of 4) was observed when
reaction was carried out without catalyst in dioxane. Loss
Figure 5a. Time change of absorbance during reaction kin1 in 2-
propanol at 40°.
of the aldehyde 1 (R = CH ) is clearly visible in the area
3
of its absorption maxima at ꢁ = 308 nm. Reactivity of
intermediate 4 is dependent on reaction conditions. It does
not react further to the product 3 without 4-toluene-
sulfonic acid. Addition of catalyst leads directly to pyra-
zolo[3,4-b]pyridine 3 (Figure 4).
Unlike in dioxane, the intermediate of reaction kin1 (5,
resp. 6) in alcoholic reaction media reacts further without
catalyst to 2-alkoxy-6-methyl-3-(3-methyl-1-phenyl-
pyrazol-5-ylaminomethylene)chroman-4-one 7. Its
formation is discernible in absorption spectra as an
appearance of new absorption band at ꢁ = 400 nm.
Evidence of its presence in reaction mixture was
confirmed by fluorescence emission spectra. As it is
shown on Figure 5a, the rate of formation of 5, resp. 6 is
higher than the rate of subsequent reaction, formation of 7
Figure 5b. Change of UV-VIS spectra during reaction kin1 in 2-
propanol.

8
46
H. Stankoviꢀová, A. Gáplovskꢁ, M. Lácová, J. Chovancová, A. Puchaꢂa
Vol 43
Presence of 4-toluenesulfonic acid in reaction
mixture significantly influences the reactivity of
intermediates 4-6 in all reaction media (Figures 4, 6
and 7). It was found that fast increase of
concentration of intermediate 5, resp. 6 occurs when
the reaction was carried out in 2-propanol (Figure 6).
This concentration decreases approximately after
1
4
00 minutes. Similarly, decrease of absorbance at ꢀ
00 nm (compound 7) was observed, its
concentration is significantly lower than in case of
uncatalyzed reaction. The findings for methanol are
similar (Figure 7). The concentration of 7 is very
low in the presence of catalyst and does not change
during reaction. Concentration of chroman-4-one 7
increases in the case of catalyzed reaction. The
results show clearly that 4-toluenesulfonic acid
catalyses transformation of 7 to pyrazolo[3,4-b]-
pyridine 3.
Figure 7. Time change od absorbance during reaction 1 with 2 in
methanol (20°).
structures. NMR spectra recorded immediately after
mixing 1 (R = NO ) and 2 in CD OD revealed a signal
2
3
at ꢁ 5.41 ppm due to methoxyacetal CH group (the
signal ppm for acetal derived from aldehyde is at ꢁ
5
.56) and a signal for phenolic OH group at ꢁ 8.21
ppm, signal for CHO group was not found. The same
spectra were recorded when pyrazole 2 was added to
the mixture of 1 and catalyst in CD OD (i.e. acetal) at
3
room temperature. The structure of intermediate
corresponds to structure formed after nucleophilic
attack to the pyrone C-2 position and subsequent ring
opening. Compound 7 is formed also by uncatalyzed
reaction from acetal 5, resp. hemiacetal 6. Similar
reactivity was found also for other substrates [18]. The
reason for this ring closure can be a formation of a
stable hydrogen bond [18,19] or ketoamine hydrogen
bond [20]. Formation of 2-hydroxy analogue of 7 was
not proved when the reaction was carried out in the
presence of catalyst in dioxane. The acid catalyzed
annelation of 4 to pyrazolo[3,4-b]pyridine was the only
one observed process in dioxane.
Figure 6. Time change of absorbance during reaction kin2 in 2-propanol
at 40°.
2
-Methoxy-6-methyl-3-(3-methyl-1-phenylpyrazol-
5
-ylaminomethylene)chroman-4-one 7 was isolated
from reaction mixture at low temperature (-15º) and
we performed kinetic measurements of its transfor-
mation to 5-(2-hydroxy-5-methylbenzoyl)-3-methyl-1-
phenyl-1H-pyrazolo[3,4-b]pyridine (3). The results
show unambigously that 3 is formed from 7 (Figure 8).
We have not found so clear evidence for direct
transformation of intermediates 5, resp. 6 to compound
EXPERIMENTAL
General.
3
. We suppose that like in dioxane product 3 is also
Melting points (uncorrected) were measured on a Kofler hot
formed directly from 5, resp. 6 by a competitive
process to the formation of chroman-4-one 7. A direct
proof is missing because we were not able to isolate
intermediates 5, resp. 6 from reaction mixtures. The
different reactivity of intermediates in protic and
aprotic solvents indicates various intermediate
stage. The NMR spectra were recorded in CDCl on Varian
3
Gemini 2000 spectrometer. UV-VIS spectra were recorded
on Hewlett-Packard ‘Diode Array 8254’ spectrometer.
Fluorescence spectra were taken in dioxane on a Hitachi F2000
spectrometer (S , S = 10 nm). Elemental analyses were
1
2
performed on a Carlo Erba Strumentacione 1106 apparatus.

Jul-Aug 2006
Transformation of 4-oxo-4H-[1]-benzopyran-3-carboxaldehydes
into pyrazolo[3,4-b]pyridines
847
Synthesis.
Commercial chemicals (solvents, 4-toluenesulfonic acid) were
used after purification (if their purity was < 99%). 6-Methyl-4-
oxo-4H-[1]-benzopyran-3-carboxaldehyde 1 [4] and 5-amino-3-
methyl-1-phenylpyrazole 2 [21] were prepared according to
literature procedures.
5
-(2-Hydroxy-5-methylbenzoyl)-3-methyl-1-phenyl-1H-pyra-
zolo[3,4-b]pyridine (3).
A solution of 5-amino-3-methyl-1-phenylpyrazole (199 mg,
1
.148 mmol) in 4 mL of ethanol was added to a stirred solution
of 6-methyl-4-oxo-4H-[1]-benzopyran-3-carboxaldehyde (216
mg, 1.148 mmol) and 4-toluenesulfonic acid (5 mg, 0.029
mmol) in 4 mL of ethanol, and the mixture was refluxed for 45
minutes. After cooling, the yellow precipitate was collected by
filtration, washed with ethanol, dried and recrystallized from
1
ethanol. Yield 85%, mp 145-146º; H NMR (300 MHz): 2.27 (s,
3
H, (CH3)benzene), 2.72 (s, 3H, (CH3)pyrazole), 7.04 (d, 1H, Ho-OH, J =
Figure 8a. Change of UV-VIS spectra during reaction kin3 in methanol
7.7Hz), 7.34 (tt, 1H, Hphenyl, J = 7.6Hz, J = 1.1Hz), 7.38 (dd, 1H,
Hp-CO, J = 7.7Hz, J = 0.8Hz), 7.39 (d, 1H, Ho-CO, J = 0.8Hz), 7.55
-
4
-3
(t = 40°; ccat = 5x10 mol.dm ).
(t, 2H, Hphenyl, J = 7.6Hz, J = 1.1Hz), 8.26 (dd, 2H, Hphenyl, J =
7
.6Hz, J = 1.1Hz,), 8.47 (d, 1H, Hpyr-ꢁ, J = 1.9Hz), 8.94 (d, 1H,
H
pyr-ꢂ, J = 1.9Hz), 11.67 (s, 1H, OH).
Anal. Calcd. for C H N O : C, 73.45; H, 4.99; N, 12.24.
2
1
17
3
2
Found: C, 73.26; H, 4.85; N 12.32%.
2
-Methoxy-6-methyl-3-(3-methyl-1-phenylpyrazol-5-ylamino-
methylene)chroman-4-one (7).
A solution of 5-amino-3-methyl-1-phenylpyrazole (199 mg,
1
.148 mmol) and 6-methyl-4-oxo-4H-[1]-benzopyran-3-
carboxaldehyde (216 mg, 1.148 mmol) in 6 mL of methanol was
stirred at –5° for 20 minutes. A precipitate was formed. A crystal
of 4-toluenesulfonic acid was added to the reaction mixture at
0
°. The previously formed precipitate was dissolved and a new
light yellow precipitate was formed in course of 10 minutes. The
product was collected by filtration, washed with methanol at 0-
1
5
2
° and dried. Yield 40%, mp 154-156°, H NMR (300 MHz):
.37 (s, 3H, (CH3)chromane), 2.50 (s, 3H, (CH3)pyrazole), 3.48 (s, 3H,
Figure 8b. Absorbance at ꢀ = 400 nm probing the loss of 7 as a function
of time in methanol, illustrating the dependence of reaction rate on
catalyst concentration.
OCH ), 6.25 (s, 1H, H-2), 7.32 (d, 1H, H-8, J = 7.2Hz), 7.40-
3
7
7
1
.48 (m, 3H, Hphenyl), 7.52 (dd, 1H, H-7, J = 7,2Hz, J = 1.5Hz),
.65-7.68 (m, 2H, Hphenyl), 8.08 (d, 1H, H-5, J = 1.5Hz), 8.68 (s,
H, H-9), 8.99 (s, 1H, Hpyrazole), 11.69 (s, 1H, NH).
Anal. Calcd for C H N O : C, 70.38; H, 5.64; N, 11.19.
2
2
21
3
3
Found: C, 70.35; H, 5.55; N 11.05%.
Kinetics.
All measurements were performed in a 1-cm thick absorption
cell at 40 or 20°. The kinetics of reactions was monitored via
UV-VIS spectrophotometry using a Hewlett-Packard ‘Diode
Array 8254’ spectrometer. Kinetic experiments were measured
until the limiting equilibrium concentration was reached.
Kin1: A solution of 6-methyl-4-oxo-4H-[1]-benzopyran-3-
-4
-3
carboxaldehyde 1 (4 mL, c = 2x10 mol.dm ) and a solution of
-
4
5
-amino-3-methyl-1-phenylpyrazole 2 (4 mL, c = 2x10
-
3
mol.dm ) in appropriate solvents were separately heated to 40 or
2
0° and mixed.
Kin2: A solution of 6-methyl-4-oxo-4H-[1]-benzopyran-3-
-
4
-3
Figure 8c. Absorbance at ꢀ = 340 nm probing the increase of 3 as a
function of time in methanol, illustrating the dependence of reaction rate
on catalyst concentration.
carboxaldehyde 1 (4 mL, c = 2x10 mol.dm ) and a solution of
-4
5-amino-3-methyl-1-phenylpyrazole 2 (4 mL,
mol.dm ) in appropriate solvents were mixed and the mixture
c
=
2x10
-
3

8
48
H. Stankoviꢀová, A. Gáplovskꢁ, M. Lácová, J. Chovancová, A. Puchaꢂa
Vol 43
was heated at 40 or 20° for 24 hours. A solution of 4-
toluenesulfonic acid (0.2 ml, c = 3x10 mol.dm ) in appropriate
solvent was added to the mixture.
[7] H. Harnisch, Liebigs Ann. Chem., 765, 8 (1972).
8] S. Klutchko, M. P. Cohen, J. Shavel Jr., M. von Strandtmann,
J. Heterocyclic Chem., 11, 183 (1974).
9] G. J. P. Becket, G.P.Ellis, Tetrahedron Lett., 17, 719 (1976).
10] D. Kaminsky, U. S. Patent 3,912,760 (1975); Chem. Abstr,.
4, 30891t (1976).
11] G. J. P. Becket, G. P. Ellis, M. I. U. Trindade, J. Chem. Res.
S), 1978, 47.
-2
-3
[
[
Kin3:
A solution of 2-methoxy-6-methyl-3-(3-methyl-1-
[
phenylpyrazol-5-ylaminomethylene)chroman-4-one 7 (3 mL, c =
8
-
4
-3
1
4
0 mol.dm ) was heated to 40° and then mixed with solution of
[
-toluenesulfonic acid.
(
[
12] S. Klutchko, D. Kaminsky, M. von Strandtmann, U. S. Patent
Acknowledgement.
4
,098,799 (1978); Chem. Abstr., 90, 22813c (1979).
[
13] Stankoviꢀová, M. Lácová, A. Gáplovskꢁ, J. Chovancová, N.
Prónayová, Tetrahedron, 57, 3455 (2001).
14] B. M. Lynch, M. A. Khan, H. C. Teo, F. Pendrotti, Can. J.
Chem., 66, 420 (1988).
15] G. Haas, J. L. Stanton, A. von Sprecher, P. Wenk, J.
Heterocyclic Chem., 18, 607 (1981).
16] D. Heber, Arch. Pharm., 316, 55 (1983).
[17] J. Quiroga, D. Mejía, B. Insuasty, R. Abonía, M. Nogueras,
A. Sánchez, J. Cobo, J. N. Low, J. Heterocyclic Chem., 39, 51 (2002).
[18] H. Stankoviꢀová, Ph.D. Thesis, Comenius University
Bratislava (1998).
We are grateful to the Slovak Grant Agency (Grant No
1
/0089/03) for support of this research.
[
[
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