Ethyl 5-amino-3-oxo-1,2-dihydro-1h-pyrazole-1-carboxylate in the selective synthesis of partially hydrogenated pyrazolo[3,4-b]pyridin-3-ones

Article abstract of DOI:10.1007/s10593-012-0999-x

Ethyl 5-amino-3-oxo-1,2-dihydro-1H-pyrazole-1-carboxylate undergoes selective cyclocondensation with 1,3-dicarbonyl compounds or their synthetic equivalents to give ethyl 3-oxo-1,2-dihydropyrazolo[3,4-b]pyridine-1- carboxylates which are readily converted

Full text of DOI:10.1007/s10593-012-0999-x

Chemistry of Heterocyclic Compounds, Vol. 48, No. 2, May, 2012 (Russian Original Vol. 48, No. 2, February, 2012)
ETHYL 5-AMINO-3-OXO-1,2-DIHYDRO-1H-PYRAZOLE-
1-CARBOXYLATE IN THE SELECTIVE SYNTHESIS OF
PARTIALLY HYDROGENATED PYRAZOLO[3,4-b]PYRIDIN-
3-ONES
P. S. Lebed'1*, N. G. Mozgovaya1, P. O. Kos1, and M. V. Vovk1
Ethyl 5-amino-3-oxo-1,2-dihydro-1H-pyrazole-1-carboxylate undergoes selective cyclocondensation
with 1,3-dicarbonyl compounds or their synthetic equivalents to give ethyl 3-oxo-1,2-dihydro-
pyrazolo[3,4-b]pyridine-1-carboxylates which are readily converted to their 1-unsubstituted analogs.
Keywords: 5-amino-1-ethoxycarbonyl-1,2-dihydro-1H-pyrazol-3-one, 5-aminopyrazol-3-one, 1,3-di-
carbonyl compounds, pyrazolo[3,4-b]pyridin-3-ones, cyclocondensation.
Partially hydrogenated pyrazolo[3,4-b]pyridin-3-ones are a biologically important and promising type
of fused heterocyclic system. They include compounds with pronounced antispasmodic [1], antidepressant [2],
and cytotoxic [3] activity and are also able to inhibit hormone-sensitive lipases [4, 5].
Two routes have been reported for the construction of this system: annelation of a pyrazole ring to a
2-functionalized nicotinic acid derivatives [6, 7] or the condensation of 5-amino-1,2-dihydro-3H-pyrazol-3-one
(1) with 1,3-dicarbonyl compounds. With the availability of reagents in mind, the second route is the more
acceptable even though the presence in the molecule of compound 1 of three nucleophilic centers is generally a
cause of nonselective cyclocondensation so forming, along with the target dihydropyrazolopyridinones, some
pyrazolo[1,5-a]pyrimidine derivatives due to participation of the 1-NH and 5-NH2 groups in the reaction.
As a result of the aminodihydropyrazolone 1 reaction with ethyl acetylpyruvate in acetic acid, there has
previously been obtained a mixture of ethyl 3-oxo-2,3-dihydropyrazolo[3,4-b]pyridine-4-carboxylate (80%
yield) and the corresponding 2,3-dihydropyrazolo[1,5-a]pyrimidin-2-one (10% yield) [8]. However, in many
attempts to reproduce this reported method we have found that the content of the latter product is not less than
25-30%. When the same reaction was carried out by us without solvent at 120ºC by another known method [9]
it was possible to prepare the target product in a yield no higher that 20%. According to the data in [8, 10] the
result of condensation of compound 1 with 3-oxobutanal or 1,3-diketones in acetic acid or hydrochloric acid
medium is the formation in all cases of a mixture of the corresponding dihydropyrazolo[3,4-b]pyridine and
dihydropyrazolo[1,5-a]pyrimidine. At the same time it was found that the use of the sodium or potassium salt of
_______
*To whom correspondence should be addressed, e-mail: p_lebed@rambler.ru.
1Institute of Organic Chemistry, Ukraine National Academy of Sciences, 5 Murmanska St., Kyiv 02094,
Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 390-394, February, 2012. Original
article submitted September 30, 2010; revision submitted May 16, 2011.
368
0009-3122/12/4802-0368©2012 Springer Science+Business Media, Inc.

pyrazolone 1 gave high yields of 2,3-dihydropyrazolo[3,4-b]pyridin-3-ones [10-13]. However, the sodium
salt proved ineffective in the reaction with acetoacetic ester. A satisfactory yield of the corresponding dihydro-
pyrazolo[3,4-b]pyridinedione was achieved only by carrying out the condensation in hydrochloric acid
[8, 10, 14, 15].
The data given above shows that development of a general, regiospecific method for the preparation of
partially hydrogenated pyrazolo[3,4-b]pyridin-3-ones is a very important goal. For its solution, we have studied
the possibility of protecting the nucleophilic center at atom N-1 in compound 1 by a COOEt group with
subsequent condensation of the ethoxycarbonyl derivative obtained with a series of active methylene
compounds.
It has previously been reported that reaction of compound 1 with ethyl chloroformate occurs at the C-4
atom to give the ethyl 5-amino-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2) [16]. We have found that the
reaction under the conditions given in [16] occurs at the N-1 atom to form the ethyl 5-amino-3-oxo-2,3-dihydro-
1
1
1H-pyrazole-1-carboxylate (3) and this is confirmed by H NMR spectroscopic data. Hence the H NMR
spectrum contains a singlet signal for H-4 proton at 4.63 ppm and a broad signal at 6.50 ppm for the NH2 group.
The 13C NMR spectrum shows a characteristic signal for the C-4 atom at 75.6 ppm.
O
COOEt
NH2
HN
2
N
H
O
ClCOOEt
HN
NH2
N
H
O
AcOH
1
5–6 h
HN
NH2
N
COOEt
3
O
R1
N
R1
R
O
O
AcOH, 18 h (5a,b);
5% NaOH (5c,d)
Me
4a–d
HN
HN
N
N
H
Me
N
Me
EtOOC
COOEt
5a–d
6a–d
O
Me
Me
O
O
Me
5% NaOH
4e
HN
HN
N
N
N
O
N
O
H
H
H
EtOOC
5e
6e
4 a R = CH(OMe)2, b R = COMe, c R = COCF3, d R = COCOOEt;
5, 6 a R1 = H, b R1 = Me, c R1 = CF3, 5d R1 = COOEt, 6d R1 = COOH
Study of the reaction of compound 3 with compounds 4a-e (with an active methylene group) has shown
that it can be successfully used in a regiospecific synthesis of both known and novel dihydropyrazolo[3,4-b]-
pyridin-3-ones. Hence in the cases of its cyclocondensation with 3-oxobutanal acetal 4a and with acetylacetone
(4b), 1H NMR and chromato-mass spectrometric analyses have shown that six-hour refluxing of the reagents in
acetic acid gives both the 1-ethoxycarbonyl-substituted compounds 5a,b in 10-15% yields and also their
decarboxylation products 6a,b. A further 18-hour refluxing of the reaction mixture allows the latter to be
369

obtained in 50-53% yields. In the case of the trifluoroacetylacetone 4c, the ester 5c formed does not undergo
decarboxylation under the conditions given and its conversion to compound 6c (in 89% yield) requires refluxing
for 0.5 h in 5% aqueous NaOH solution. Similarly the ethyl acetylpyruvate 4d gives an 83% yield of diester 5d,
alkaline treatment of which gives the acid 6d in almost quantitative yield. The reported reaction can be regarded
as a novel and convenient method for the preparation of 6-alkyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyri-
dine-4-carboxylic acids. Use of the 1-ethoxycarbonyl-substituted compound 3 in reaction with the acetoacetate
4e has preparative value when compared with the analog unsubstituted at N-1 since the 2,3,6,7-tetrahydro-
pyrazolo[3,4-b]pyridine-3,6-dione 5e is formed virtually pure and is readily hydrolyzed using 5% NaOH to give
the target compound 6e in 96% yield.
Hence preliminary N(1)-acylation of 5-amino-1,2-dihydropyrazol-3-one using chloroformate is an
efficient variant which increases the selectivity of its reaction with 1,3-dicarbonyl compounds or their synthetic
equivalents.
EXPERIMENTAL
IR spectra were recorded on a UR-20 instrument using KBr pellets. 1H NMR and 13C NMR spectra were
recorded on a Bruker Avance DRX-500 spectrometer (500 and 125 MHz, respectively) using DMSO-d6 with
TMS as internal standard.
The starting compound 1 was prepared using method [17].
Ethyl 5-amino-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate (3) was prepared by method [16].
Yield 56%; mp 155-157ºC (mp 155-160ºC [16]). 1H NMR spectrum, , ppm (J, Hz): 1.34 (3H, t, J = 7.0, CH3);
4.30 (2H, q, J = 7.0, CH2); 4.63 (1H, s, H-4); 6.50 (2H, br. s, NH2); 10.19 (1H, br. s, NH). 13C NMR spectrum,
, ppm: 14.0 (CH3); 62.7 (CH2); 75.6 (C-4); 150.5 (C=O); 153.0 (C-5); 165.2 (C=O).
Pyrazolo[3,4-b]pyridine-1-carboxylic Acid Derivatives 5c-e (General Method). A mixture of
compound 3 (2.5 mmol) and trifluoroacetylacetone (4c), ethyl acetylpyruvate (4d), or acetoacetic ester (4e)
(2.5 mmol) was refluxed in glacial acetic acid (8 ml) for 5-6 h. The corresponding precipitated product 5
obtained on cooling was filtered off, washed with water, dried, and recrystallized from ethanol.
Ethyl
6-Methyl-3-oxo-4-trifluoromethyl-2,3-dihydro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate
1
(5c). Yield 81%; mp 177-178ºC. IR spectrum, , cm-1: 1735 (C=O), 1760 (C=O), 3350 (N–H). H NMR
spectrum, , ppm (J, Hz): 1.37 (3H, t, J = 7.0, CH2CH3); 2.72 (3H, s, 6-CH3); 4.43 (2H, q, J = 7.0, CH2CH3);
7.67 (1H, s, H-5); 12.26 (1H, br. s, NH). Found, %: C 45.71; H 3.47; N 14.50. C11H10F3N3O3. Calculated, %:
C 45.68; H 3.49; N 14.53.
Diethyl 6-Methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridine-1,4-dicarboxylate (5d). Yield
1
83%; mp 221-222ºC (decomp.). IR spectrum, , cm-1: 1690 (C=O), 1760 (C=O), 3450 (N–H). H NMR
spectrum, , ppm (J, Hz): 1.42 (6H, m, CH2CH3); 2.71 (3H, s, 6-CH3); 4.44 (4H, m, CH2CH3); 7.51 (1H, s,
H-5); 11.74 (1H, br. s, NH). Found, %: C 53.17; H 5.17; N 14.31. C13H15N3O5. Calculated, %: C 53.24; H 5.16;
N 14.33.
Ethyl 4-Methyl-3,6-dioxo-2,3,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (5e). Yield
1
48%; mp 237-239ºC (decomp.). IR spectrum, , cm-1: 1675 (C=O), 1725 (C=O), 3345 (N–H). H NMR
spectrum, , ppm (J, Hz): 1.32 (3H, t, J = 7.0, CH2CH3); 2.39 (3H, s, 4-CH3); 4.36 (2H, q, J = 7.0, CH2CH3);
6.21 (1H, s, H-5); 11.49 (1H, br. s, NH). Found, %: C 50.59; H 4.59; N 17.70. C10H11N3O4. Calculated, %:
C 50.63; H 4.67; N 17.71.
6-Methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-ones (6a,b) (General Method). A mixture of
compound 3 (0.43 g, 2.5 mmol) and 3-oxobutanal dimethylacetal (4a) or acetylacetone (4b) (2.5 mmol) was
refluxed in glacial acetic acid (8 ml) for 24 h. The solvent was evaporated and the residue was recrystallized
from ethanol.
370

6-Methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (6a). Yield 53%; mp 278-280ºC (mp
282-283ºC [8]). 1H NMR spectrum, , ppm (J, Hz): 2.49 (3H, s, 6-CH3); 6.21 (1H, d, J = 7.9, H-4); 6.90 (1H, d,
J = 7.9, H-5); 11.36 (2H, br. s, NH). Found, %: C 56.39; H 4.78; N 28.15. C7H7N3O. Calculated, %: C 56.37;
H 4.73; N 28.17.
4,6-Dimethyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (6b). Yield 50%; mp  300ºC (mp 355ºC
[8, 10]). 1H NMR spectrum, , ppm (J, Hz): 2.44 (3H, s, CH3); 2.51 (3H, s, CH3); 6.67 (1H, s, H-5); 11.16 (2H,
br. s, NH). Found, %: C 58.91; H 5.59; N 25.72. C8H9N3O. Calculated, %: C 58.89; H 5.56; N 25.75.
6-Methyl-4-trifluoromethyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (6c), 6-Methyl-3-oxo-
2,3-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic Acid (6d), 4-Methyl-1H-pyrazolo[3,4-b]pyridine-
3,6(2H,7H)-dione (6e) (General Method). A suspension of compound 5c-e (1.4 mmol) in 5% aqueous NaOH
solution (10 ml) was refluxed for 0.5 h, cooled, acidified with dilute HCl solution to pH 5, and the precipitate
formed was filtered off, washed with water, and dried.
6-Methyl-4-trifluoromethyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (6c). Yield 89%; mp
1
253-254ºC (mp 255-256ºC [11]). H NMR spectrum, , ppm (J, Hz): 2.61 (3H, s, 6-CH3); 7.27 (1H, s, H-5);
11.09 (1H, br. s, NH); 12.48 (1H, br. s, NH). Found, %: C 44.26; H 2.80; N 19.33. C8H6F3N3O. Calculated, %:
44.25; H 2.79; N 19.35.
6-Methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic Acid (6d). Yield 95%;
mp > 300ºC. IR spectrum, , cm-1: 1650 (C=O), 1680 (C=O), 3410 (N–H), 3480 (N–H). 1H NMR spectrum, ,
ppm (J, Hz): 2.56 (3H, s, CH3); 7.30 (1H, s, H-5). Found, %: C 49.73; H 3.67; N 21.70. C8H7N3O3. Calculated,
%: C 49.75; H 3.65; N 21.75.
4-Methyl-1H-pyrazolo[3,4-b]pyridine-3,6(2H,7H)-dione (6e). Yield 96%; mp > 300ºC (mp > 300ºC
1
[8, 10]). H NMR spectrum, , ppm (J, Hz): 2.32 (3H, s, 4-CH3); 5.78 (1H, s, H-5); 11.11 (2H, br. s, NH).
Found, %: C 50.88; H 4.30; N 25.41. C7H7N3O2. Calculated, %: C 50.91; H 4.27; N 25.44.
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