Synthesis of 1-substituted 5-acetyl (ethoxycarbonyl)-2,3-dihydropyrazolo- [3,4-b]pyridin-3-ones

Article abstract of DOI:10.1007/s10593-012-1099-7

1-Substituted 5-aminopyrazol-3-ones react selectively with ethoxymethylidene β-dicarbonyl compounds (3-ethoxymethylidene-2,4- pentanedione, diethyl 2-ethoxymethylidenemalonate, and ethyl 2-ethoxy-methylideneacetoacetate) with the formation of dihydropyraz

Full text of DOI:10.1007/s10593-012-1099-7

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
SYNTHESIS OF 1-SUBSTITUTED 5-ACETYL
(ETHOXYCARBONYL)-2,3-DIHYDROPYRAZOLO-
[3,4-b]PYRIDIN-3-ONES
P. S. Lebed'1*, N. G. Mozgovaya1, O. V. Manoilenko2,
V. S. Tolmachova3, and M. V. Vovk1
1-Substituted 5-aminopyrazol-3-ones react selectively with ethoxymethylidene β-dicarbonyl compounds
(3-ethoxymethylidene-2,4-pentanedione, diethyl 2-ethoxymethylidenemalonate, and ethyl 2-ethoxy-
methylideneacetoacetate) with the formation of dihydropyrazolylaminomethylidene β-dicarbonyl
derivatives, which undergo thermal intramolecular cyclization to 5-functionalized dihydro-
pyrazolo[3,4-b]pyridin-3-ones.
Keywords: 5-acetyl-4-methyl-1,2-dihydropyrazolo[3,4-b]pyridin-3-ones, 1-substituted 5-aminopyrazol-
3-ones, ethyl 4-hydroxy-3-oxo-2,3-dihydropyrazolo[3,4-b]pyridine-5-carboxylate, ethoxymethylidene-
β-dicarbonyl compounds.
The interest in derivatives of pyrazolo[3,4-b]pyridine-5-carboxylic acid is due to their valuable
biological properties. Substances with antiherpetic [1], antimitotic [2], antiarrhythmic [3], anti-inflammatory [4],
and anxiolytic [5] activity have been found among them. Thermal intramolecular cyclization of the products
from condensation of 5-aminopyrazoles with diethyl 2-ethoxymethylidenemalonate is used for their synthesis
[3, 6-12] and allows, as a rule, to obtain condensed systems with an ethoxycarbonyl substituent in the pyridine
ring. The use of 5-aminopyrazol-3-ones as binucleophilic component [13, 14] in a reaction of such a type may
prove rather useful for the preparation of derivatives additionally functionalized in the pyrazole ring. Here it
should be noted that 1-substituted 5-aminopyrazol-3-ones have not been studied before in such transformations.
For this reason, it seemed expedient to investigate the reaction of 1-substituted 5-aminopyrazol-3-ones 1a-e
with a series of ethoxymethylidene β-dicarbonyl compounds: 3-ethoxymethyl-idene-2,4-pentanedione (2a),
diethyl 2-ethoxymethylidenemalonate (2b), and ethyl 2-ethoxymethylidene-acetoacetate (2c).
_______
*To whom correspondence should be addressed, e-mail: p_lebed@rambler.ru.
1Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02094,
Ukraine.
2Kyiv Taras Shevchenko National University, 62 Volodymirska St., Kyiv, 01033, Ukraine; e-mail:
o.manoilenko@mail.enamine.net.
3M. Dragomanov National Pedagogical University, 9 Pirogova St., Kyiv 01601, Ukraine; e-mail:
tolmachova@ukr.net.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1140-1145, July, 2012. Original
article submitted September 21, 2011.
1058
0009-3122/12/4807-1058©2012 Springer Science+Business Media New York

It was found that compounds 1a-e react with ethoxymethylidene derivatives 2a-c in refluxing dioxane with
the formation of the condensation products 3a-i, which are high-melting crystalline substances (yields 49-80%). The
1H NMR spectra of compounds 3a-i are characterized by singlets for the H-4 protons of the pyrazolone ring at
5.52-6.13 ppm and by doublets of the NH and =CH group protons of the exocyclic enamine fragment at
10.62-12.77 and 7.96-8.18 ppm respectively, with spin-spin coupling constants of 11-12 Hz.
When heated in diphenyl ether at 250°C for 1 h, the compounds 3a-e undergo intramolecular cyclo-
condensation with the formation of 5-acetyl-4-methyl-1,2-dihydropyrazolo[3,4-b]pyridin-3-ones 4a-e with
yields of 52-65%. Under analogous conditions, compounds 3f-h are converted into ethyl 4-hydroxy-3-oxo-
2,3-dihydropyrazolo[3,4-b]pyridine-5-carboxylates 5a-c with somewhat smaller yields (43-50%). In the case of
compound 3i, obtained by the reaction of 5-aminopyrazol-3-one 1a with the unsymmetrical ethoxymethylidene
derivative 2c, thermal cyclization takes place nonselectively and leads to a mixture of 5-acetyl-4-hydroxy-
1,2-dihydropyrazolo[3,4-b]pyridin-3-one 6 and ethyl 4-methyl-3-oxo-2,3-dihydropyrazolo[3,4-b]pyridine-
5-carboxylate 7, which are formed in a ratio of 5:1, according to the chromato-mass spectroscopy data. It was
possible to separate compounds 6 and 7 by preparative liquid chromatography.
The formation of the dihydropyrazolo[3,4-b]pyridine ring in all types of compounds 4-7 is confirmed by
the presence of singlets for the H-6 protons at 8.69-9.01 ppm in their 1H NMR spectra and of signals for the C-4
atoms in the region of 135-148 ppm (for compounds 4 and 7) and 166-171 ppm (for compounds 5 and 6), for
C-5 in the region of 105-110 ppm (for compounds 5 and 6), 117 ppm (for compound 7), and 125-127 ppm (for
compound 4), and also for C-6 in the region of 146-153 ppm in their 13C NMR spectra.
O
O
O
Me
O
O
R1 = R2 = Me
O
O
Me
OEt
Me
HN
R1
R2
N
HN
N
+
NH2
N
R
4a–e
EtO
R
1a–e
2a–c
OH
O
1,4-Dioxane
, 4 h
R1 = R2 = CO2Et
HN
N
N
O
R1
R
Ph2O
250°C, 1 h
5a–c
HN
OH
N
O
O
N
R
H
R2
3a–i
O
HN
N
N
6
+
Me
R1 = Me, R2 = CO2Et
O
Me
O
OEt
HN
N
N
Me
7
1a R = Me, 1b R = Ph, 1c R = 4-FC6H4, 1d R = 4-ClC6H4, 1e R = Bn; 2a R1 = R2 = Me,
2b R1 = R2 = OEt, 2c R1 = Me, R2 = OEt; 3a R = R1 = R2 = Me; 3b R = Ph, R1 = R2 = Me;
3c R = 4-FC6H4, R1 = R2 = Me; 3d R = 4-ClC6H4, R1 = R2 = Me; 3e R = Bn, R1 = R2 = Me;
3f R = Me, R1 = R2 = OEt; 3g R = Ph, R1 = R2 = OEt; 3h R = 4-FC6H4, R1 = R2 = OEt;
3i R = R1 = Me, R2 = OEt; 4a R = Me, 4b R = Ph, 4c R = 4-FC6H4, 4d R = 4-ClC6H4, 4e R = Bn;
5a R = Me, 5b R = Ph, 5c R = 4-FC6H4
1059

TABLE 1. The Physicochemical Characteristics of Compounds 3a-i, 4a-e,
5a-c, 6, and 7
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
Mp*, °С
C
H
N
3a
3b
3c
3d
3e
3f
C10H13N3O3
C15H15N3O3
C15H14FN3O3
C15H14ClN3O3
C16H17N3O3
C12H17N3O5
C17H19N3O5
C17H18FN3O5
C11H15N3O4
C10H11N3O2
C15H13N3O2
C15H12FN3O2
C15H12ClN3O2
C16H15N3O2
C10H11N3O4
C15H13N3O4
C15H12FN3O4
C9H9N3O3
53.60
53.81
62.98
63.15
59.55
59.40
55.95
56.35
64.04
64.20
51.01
50.88
59.37
59.12
56.28
56.50
52.29
52.17
58.40
58.53
67.12
67.41
62.89
63.15
59.51
59.71
67.99
68.31
50.32
50.63
60.22
60.20
5.75
5.87
5.18
5.30
4.59
4.65
4.32
4.41
5.65
5.72
5.93
6.05
5.57
5.55
5.10
4.99
6.06
5.97
5.47
5.40
4.98
4.90
4.09
4.24
4.00
4.01
5.27
5.37
4.46
4.67
4.30
4.38
18.80
18.82
14.66
14.73
13.98
13.85
13.05
13.14
14.11
14.04
15.00
14.83
12.29
12.17
11.49
11.56
16.61
16.59
20.50
20.48
15.80
15.72
14.81
14.73
14.04
13.93
15.03
14.94
17.59
17.71
14.13
14.04
224-225
223-224
211-212
239-240
193-194
195-196
228-229
210-211
194-195
224-225
237-238
245-246
244-246
204-205
217-218
212-213
213-215
211-212
193-194
78
65
78
75
72
80
49
52
80
58
59
65
59
52
43
47
50
21
5
3g
3h
3i
4a
4b
4c
4d
4e
5a
5b
5c
6
56.50
56.79
52.32
52.17
55.95
56.16
3.92
3.81
4.30
4.38
5.43
5.57
13.31
13.24
20.40
20.28
17.89
17.86
7
C11H13N3O3
______
*Solvents for recrystallization: dioxane (compounds 3a,c,d,f-i, 5c), MeOH
(compound 3b), EtOH (compounds 3e, 4e) DMF (compound 4a), and AcOH
(compounds 4b-d, 5a,b).
The experimental results indicate that the structure of the electrophilic component (the
ethoxymethylidene β-dicarbonyl compounds 2a-c) has practically no effect on the yields of the primary
condensation products 3a-i. The thermal transformation of the latter is controlled by the substituents R1 and R2
and, in the case where they are non-equivalent, is accompanied by nonselective occurrence of the process and
by low yields of the products 6 and 7.
Thus, we have proposed an effective method for the synthesis of new 5-acetyl(ethoxycarbonyl)-
dihydropyrazolo[3,4-b]pyridin-3-ones based on the cyclocondensation of 1-substituted 5-aminopyrazol-3-ones
with 2-ethoxymethylidene derivatives of acetylacetone and malonic ester.
1060

TABLE 2. The IR and 1H NMR Spectra of Compounds 3a-i, 4a-e, 5a-c, 6, and 7
IR
Com-
pound
1Н NMR, δ, ppm (J, Hz)
spectrum*,
νС=О, cm-1
3а
1625
1630
2.36 (3Н, s, СН3); 2.40 (3Н, s, СН3); 3.53 (3Н, s, СН3); 5.77 (1Н, s, Н-4);
8.09 (1Н, d, J = 11.6, =СН); 9.84 (1Н, s, NH); 12.57 (1Н, d, J = 11.2, NH)
3b
2.33 (3Н, s, СН3); 2.51 (3Н, s, СН3); 6.11 (1Н, s, Н-4);
7.46-7.62 (5Н, m, H Ph); 8.05 (1Н, d, J = 11.3, =СН); 10.37 (1Н, s, NH);
12.76 (1Н, d, J = 11.6, NH)
3c
3d
3e
3f
1625
1640
1625
1695
1685
2.32 (3Н, s, СН3); 2.33 (3Н, s, СН3); 6.12 (1Н, s, Н-4);
7.40-7.57 (4H, m, H Ar); 8.18 (1Н, d, J = 12.0, =СН);
10.37 (1Н, br. s, NH); 12.76 (1Н, d, J = 11.2, NH)
2.33 (3Н, s, СН3); 2.34 (3Н, s, СН3); 6.13 (1Н, s, Н-4);
7.42-7.56 (4Н, m, H Ar); 8.17 (1Н, d, J = 9.2, =СН);
10.36 (1Н, br. s, NH); 12.77 (1Н, d, J = 8.4, NH)
2.29 (3Н, s, СН3); 2.37 (3Н, s, СН3); 5.09 (2Н, s, СН2Ph);
5.87 (1Н, s, Н-4); 7.16-7.37 (5Н, m, H Ph); 8.11 (1Н, d, J = 12.0, =СН);
10.02 (1Н, br. s, NH); 12.73 (1Н, d, J = 11.6, NH)
1.20-1.27 (6H, m, 2CH2CH3); 3.49 (3H, s, CH3);
4.11-4.19 (4H, m, 2CH2CH3); 5.52 (1Н, s, Н-4);
7.96 (1Н, d, J = 11.7, =СН); 9.85 (1Н, br. s, NH); 10.39 (1Н, br. s, NH)
3g
1.16-1.24 (6H, m, 2CH2CH3); 4.08-4.12 (4H, m, 2CH2CH3);
5.89 (1Н, s, Н-4); 7.39-7.51 (5Н, m, H Ph); 8.07(1Н, d, J = 12.4, =СН);
10.31 (1Н, s, NH); 10.70 (1Н, d, J = 14.4, NH)
3h
3i
1640,
1690
1.15-1.22 (6H, m, 2CH2CH3); 4.07-4.15 (4H, m, 2CH2CH3);
5.87 (1Н, s, Н-4); 7.37-7.55 (4Н, m, H Ar); 8.67 (1Н, d, J = 11.2, =СН);
10.33 (1Н, br. s, NH); 10.62 (1Н, d, J = 12.0, NH)
1700
1.24 (3Н, t, J = 7.0, CH2CH3); 2.43 (3Н, s, СН3); 3.57 (3Н, s, СН3);
4.15 (2H, q, J = 7.0, CH2CH3); 5.62 (1Н, s, Н-4);
8.07 (1Н, d, J = 11.6, =СН); 9.81 (1Н, s, NH); 12.57 (1Н, br. s, NH)
4a
4b
4c
4d
4e
5a
1670
1678
1685
1680
1675
1672
2.61 (3Н, s, СН3); 2.81 (3Н, s, СН3); 3.80 (3Н, s, СН3); 8.88 (1Н, s, Н-6);
11.44 (1Н, br. s, NH)
2.65 (3Н, s, СН3); 2.86 (3Н, s, СН3); 7.52-8.21 (5Н, m, H Ph);
9.01 (1Н, s, Н-6); 12.10 (1Н, br. s, NH)
2.64 (3Н, s, СН3); 2.83 (3Н, s, СН3); 7.35-8.18 (4Н, m, H Ar);
8.98 (1Н, s, Н-6); 12.12 (1Н, br. s, NH)
2.64 (3Н, s, СН3); 2.82 (3Н, s, СН3); 7.56-8.22 (4Н, m, H Ar);
8.98 (1Н, s, Н-6); 12.15 (1Н, br. s, NH)
2.63 (3Н, s, СН3); 2.82 (3Н, s, СН3); 5.43 (2Н, s, СН2Ph);
7.16-7.37 (5Н, m, H Ph); 8.98 (1Н, s, Н-6); 11.57 (1Н, br. s, NH)
1.37 (3Н, t, J = 7.0, CH2CH3); 3.78 (3Н, s, СН3);
4.40 (2H, q, J = 7.0, CH2CH3); 8.69 (1Н, s, Н-6); 11.24 (1H, br. s, NH);
12.06 (1H, br. s, OH)
5b
5c
1660
1670
1.09 (3Н, t, J = 7.0, CH2CH3); 4.40 (2H, q, J = 7.0, CH2CH3);
7.50-8.12 (5H, m, H Ph); 8.77 (1Н, s, Н-6); 11.82 (1H, br. s, NH);
11.99 (1H, br. s, OH)
1.34 (3H, t, J = 7.0, CH2CH3); 4.38 (2H, q, J = 7.0, CH2CH3);
6.99-7.35 (4H, m, H Ar); 8.74 (1Н, s, Н-6); 11.90 (1H, br. s, NH);
11.96 (1H, br. s, OH)
6
7
1655
1710
2.66 (3Н, s, СН3); 3.77 (3Н, s, СН3); 8.79 (1H, br. s, H-6);
11.29 (1H, br. s, NH)*2
1.34 (3H, t, J = 7.0, CH2CH3); 2.86 (3Н, s, СН3); 3.80 (3Н, s, СН3);
4.30 (2H, q, J = 7.0, CH2CH3); 8.82 (1Н, s, Н-6); 11.45 (1H, br. s, NH)
_______
*The absorption of the OH and NH groups appears in the form of difficult to
identify broad bands in the region of 3200-3450 cm-1.
*2The proton of the OH group does not appear on account of deuterium
exchange with water present in the solvent.
1061

TABLE 3. The 13C NMR Spectra of Compounds 4a-e, 5a-c, 6, and 7
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
16.8 (4-CH3); 30.4 (CH3); 33.2 (1-CH3); 105.4 (C-3a); 125.5 (C-5); 147.1 (C-4);
4а
150.8 (C-7a); 152.6 (C-6); 155.7 (C-3); 199.2 (С=О)
16.6 (4-CH3); 30.5 (CH3); 108.0 (C-3a); 120.0 (C Ar); 125.2 (C-5); 127.1 (C Ar);
129.5 (C Ar); 139.5 (C-4); 147.1 (C-7a); 150.3 (C Ar); 152.7 (C-6); 157.1 (C-3);
199.2 (C=O)
4b
16.5 (4-СH3); 30.4 (CH3); 107.8 (C-3a); 116.2 (d, 2JC–F = 24, C-3',5');
121.6 (d, 3JC–F = 10, C-2',6'); 126.9 (C-5); 135.9 (C-4); 147.2 (C-7а); 150.0 (C-1');
152.7 (C-6); 157.0 (C-3); 159.5 (d, 1JC–F = 241, C-4'); 199.0 (C=O)
4c
4d
4e
16.5 (4-СH3); 30.4 (CH3); 108.2 (C-3a); 121.1 (C Ar); 127.2 (С-5), 129.4 (C Ar);
138.3 (C-4); 144.1 (C Ar); 148.4 (C-7а); 150.3 (C Ar); 152.7 (C-6); 157.2 (C-3);
199.1 (C=O)
16.8 (4-CH3); 30.5 (CH3); 49.6 (CН2); 105.6 (C-3a); 125.9 (C-5); 128.0 (C Ar);
128.0 (C Ar); 129.0 (C Ar); 137.9 (C-4); 147.2 (C-7а); 150.8 (C Ar); 152.8 (C-6);
156.1 (C-3); 190.2 (C=O)
5a*
5b*
5c*
12.3 (CH2CH3); 34.9 (1-CH3); 65.0 (CH2CH3); 99.6 (C-3a); 105.6 (C-5); 143.6 (C-7a);
146.2 (C-6); 157.3 (C-3); 167.5 (C=O); 171.7 (C-4)
12.3 (CH2CH3); 65.0 (CH2CH3); 98.9 (C-3a); 104.9 (C-5); 125.0 (C Ar); 130.9 (C Ar);
132.1 (C Ar); 132.6 (C Ar); 142.8 (C-7a); 146.1 (C-6); 157.7 (C-3); 167.6 (C=O); 171.5 (C-4)
12.3 (CH2CH3); 65.1 (CH2CH3); 99.7 (C-3a); 105.7 (C-5); 118.0 (d, 2JC–F = 24, C-3',5');
128.0 (d, 3JC–F = 10, C-2',6'); 128.6 (C-1'); 143.3 (C-7a); 146.1 (C-6); 157.3 (C-3);
164.8 (d, 1JC–F = 255, C-4');167.5 (C=O); 171.7 (C-4)
27.4 (CH3); 33.6 (1-CH3); 94.8 (C-3a); 110.8 (C-5); 150.5 (C-7a); 153.8 (C-6);
155.1 (C-3); 166.7 (C-4); 204.0 (С=О)
6
7
14.7 (CH2CH3); 16.5 (4-CH3); 33.3 (1-CH3); 60.9 (CH2CH3); 105.0 (C-3a);
117.3 (C-5); 148.3 (C-4); 151.1 (C-7a); 152.2 (C-6); 155.4 (C-3); 166.3 (C=O)
_______
*The 13C NMR spectra were recorded in CF3COOH.
EXPERIMENTAL
The IR spectra were recorded in pellets with KBr on a UR-20 instrument. The 1H and 13C NMR spectra
were recorded in DMSO-d6 on a Bruker Avance DRX-500 spectrometer (500 and 125 MHz respectively) with
TMS as internal standard. Elemental analysis was performed on a Perkin Elmer CHN Analyzer. The melting
points were determined on a Kofler bench and were not corrected. Preparative liquid chromatography was
conducted on a Combi Flash Companion instrument with a two-wave UV detector with detection at 235 and 254
nm; RediSep 12g column, sorbent silica gel 40-60 μm, pore diameter 60 Å; flow rate 30 ml/min; stepwise
gradient elution.
The starting compounds were synthesized by the methods in [13] (compound 1a) and [14] (compounds
1b-e).
3-{[(2-Alkyl(aryl)-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)amino]methylidene}pentane-2,4-diones 3a-e,
Diethyl {[(2-Alkyl(aryl)-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)amino]methylidene}propanedioates 3f-h,
Ethyl 3-Oxo-2-{[(2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)amino]methylidene}butanoate (3i) (General
Method). A mixture of compound 1a-e (5 mmol) and compound 2a-c (5 mmol) in 1,4-dioxane (12 ml) was
refluxed for 4 h. After cooling, the precipitate was filtered off. The filtrate was evaporated, the residue was
crystallized with the addition of EtOH (6-8 ml), and the crystals that formed were mixed with the first portion of
the precipitate and recrystallized.
5-Acetyl-1-alkyl(aryl)-4-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-ones 4a-e, Ethyl 1-Alkyl-
(aryl)-4-hydroxy-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylates 5a-c, 5-Acetyl-4-hydroxy-
1-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (6), and Ethyl 1,4-Dimethyl-3-oxo-2,3-dihydro-
1H-pyrazolo[3,4-b]pyridine-5-carboxylate (7) (General Method). A mixture of compound 3a-i (1.5 mmol)
1062

and diphenyl ether (5 ml) was heated with stirring at a bath temperature of 250°C for 1 h. After cooling, hexane
(25 ml) was added to the reaction mixture, the mixture was thoroughly mixed, and the precipitate was filtered
off. Compounds 4a-e and 5a-c were recrystallized, and compounds 6 and 7 were isolated by preparative
chromatography (eluent CHCl3–MeCN, 3:1 and 7:3 respectively).
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