Three-component condensation of 5-aminopyrazole derivatives with isatins and Meldrums acid. Synthesis of 1, 7-dihydrospiro[pyrazolo[3, 4-b]-pyridine-4, 3' -indole]-2' , 6(1 H, 5H)-diones

Article abstract of DOI:10.1007/s11172-009-0202-4

A new method for the synthesis of hitherto unknown substituted 1, 7-dihydrospiro-[pyrazolo[3, 4-b]pyridine-4, 3'-indole]-2', 6(1'i/, 5i/)-diones based on three-component condensation of 5-aminopyrazoles with Meldrum's acid and isatins is developed.

Full text of DOI:10.1007/s11172-009-0202-4

Russian Chemical Bulletin, International Edition, Vol. 58, No. 7, pp. 1504—1508, July, 2009
1504
Threeꢀcomponent condensation of 5ꢀaminopyrazole derivatives with isatins
and Meldrum´s acid. Synthesis of 1,7ꢀdihydrospiro[pyrazolo[3,4ꢀb]ꢀ
pyridineꢀ4,3´ꢀindole]ꢀ2´,6(1´H,5H)ꢀdiones
B. V. Lichitsky, A. N. Komogortsev, A. A. Dudinov, and M. M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: mkray@ioc.ac.ru
A new method for the synthesis of hitherto unknown substituted 1,7ꢀdihydrospiroꢀ
[pyrazolo[3,4ꢀb]pyridineꢀ4,3´ꢀindole]ꢀ2´,6(1´H,5H)ꢀdiones based on threeꢀcomponent conꢀ
densation of 5ꢀaminopyrazoles with Meldrum´s acid and isatins is developed.
Key words: isatins, threeꢀcomponent condensation, Meldrum´s acid, 5ꢀaminopyrazoles,
decarboxylation, 1,7ꢀdihydrospiro[pyrazole[3,4ꢀb]pyridineꢀ4,3´ꢀindole]ꢀ2´,6(1´H,5H)ꢀdiones.
Earlier,1—6 we have developed a general method for
the synthesis of fused systems 1 containing a dihydropyriꢀ
dinone residue based on a threeꢀcomponent condensation
of labile heterocyclic amines 2 with aldehydes 3 and
Meldrum´s acid 4 (Scheme 1).
Undoubtedly, the advantage of this method is the posꢀ
sibility of production of unstable aminoheterocycles in situ
from vicinal aminocarboxylic acids 5, which are formed
upon alkaline hydrolysis of the corresponding easily acꢀ
cesible esters1,2,4 or as the result of neutralization of stable
hydrochlorides 6 with anhydrous sodium acetate.3,5,6 It is
of note that it is aromatic aldehydes that have been used in
this condensation. At the same time, it is obvious that the
extending of the panel of the aldehydes that can be used in
the described process as well as the use of ketones will
allow significant diversification of the structures of this
threeꢀcomponent condensation products.
We anticipated that isatins can be aromatic aldehyde
analogs, which will result in fused spirosystems containꢀ
ing an indolone fragment. The synthesis of spirooxyindole
systems based on the condensation of isatins with dimeꢀ
done7 and substituted 6ꢀaminouracils,8 resulting in spiroꢀ
[indolineꢀ3,9´ꢀxantene]trione and spiro[pyrimido[4,5ꢀb]ꢀ
quinolineꢀ5,5´ꢀpyrrolo[2,3ꢀd]pyrimidine]pentone derivaꢀ
tives, respectively, have been described. It is worth menꢀ
tioning that the spirooxyindole system is the key structural
fragment of many biologically active compounds and natꢀ
ural alkaloids.9—12
The aim of the present work was to synthesize hitherto
unknown substituted 1,7ꢀdihydrospiro[pyrazolo[3,4ꢀb]ꢀ
Scheme 1
1a
S
CR1
CR2
1b
1c
CR1
CR2
S
1d
N
CR1
Se
1e
CR1
N
X
Y
Z
N
CR1
S
S
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1460—1464, July, 2009.
1066ꢀ5285/09/5807ꢀ1504 © 2009 Springer Science+Business Media, Inc.

Synthesis of a spirooxoindole system
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1505
pyridineꢀ4,3´ꢀindole]ꢀ2´,6(1´H,5H)ꢀdiones 7 based on
a threeꢀcomponent condensation of 5ꢀaminopyrazole deꢀ
rivatives 8, isatins 9, and Meldrum´s acid 4 (Scheme 2).
We demonstrated that the reaction of compounds 4, 8,
and 9 leads to compounds 7 in good yields. Acids 10 necꢀ
essary for the synthesis of compounds 7 readily undergo
decarboxylation13 leading to 5ꢀaminopyrazoles 8, and can
be obtained as sodium salts by alkaline hydrolysis14 of the
corresponding esters 12.
5ꢀAminopyrazoles 8 are stable compounds, which can
be obtained in the free form from esters 12 in two steps.13
In our case, amines 8 were generated in situ from preꢀ
formed sodium salts 11a—c. The latter were obtained
upon alkaline hydrolysis of esters 12a—с and were used
in the threeꢀcomponent condensation without additional
purification.
We assume that the reaction occurs according to
one of two most probable paths (Scheme 3). Thus, isatin
can first add to 5ꢀaminopyrazole 8 giving the adduct 13,
which further reacts with Meldrum´s acid to form unꢀ
stable intermediate 14, which eliminates СO2 and acetone
(path А) affording the final product 7. An alternative
scheme of the process includes the Michael addition
of 5ꢀaminopyrazole 8 to oxoindolylidene derivative of
Meldrum´s acid 15 followed by the intermolecular cyꢀ
clization (path B).
An important feature of the reaction investigated should
be mentioned. In contrast to the previously described
methods where aromatic aldehydes have been employed,
we failed to isolate stable oxoindolylidene derivative 15 in
the condensation of Meldrum´s acid with isatin. Thus, the
approaches that have previously been applied for the
arylidene derivatives of Medrum´s acid and stable heteꢀ
rocyclic enamines15—17 are not suitable in this case.
The synthesis of the target compounds 7 can be performed
only under conditions of the threeꢀcomponent condensaꢀ
tion of 5ꢀaminopyrazole derivatives 8, isatins 9, and Melꢀ
drum´s acid 4.
The obtained compounds are solid crystalline substanꢀ
ces; their structures were confirmed by elemental analysis
and data from 1Н NMR spectroscopy (Tables 1, 2). Charꢀ
acteristic doublets of the nonꢀequivalent protons of the
methylene unit at δ 2.42—3.19 are observed in the 1Н NMR
spectra of the obtained products.
Thus, we developed a novel useful method of synthesis
of hitherto unknown substituted 1,7ꢀdihydrospiro[pyrꢀ
azolo[3,4ꢀb]pyridineꢀ4,3´ꢀindole]ꢀ2´,6(1´H,5H)ꢀdiones
based on the threeꢀcomponent condensation of 5ꢀaminoꢀ
pyrazoles, Meldrum´s acid, and isatins. It was found that
sodium 5ꢀaminopyrazoleꢀ4ꢀcarboxylates can act as synꢀ
thetic equivalents of 5ꢀaminopyrazoles. It was demonꢀ
strated that the reaction can be performed only as the
Scheme 2
11, 12: R´ = H (a), Ph (b), CMe3 (c)
Comꢀ
pound
7a
7b
7c
R´
R″
Comꢀ
pound
7e
7f
7g
R´
R″
Comꢀ
pound
7i
7j
7k
R´
R″
H
H
H
H
H
Me
Et
H
H
Ph
Ph
H2C—C≡CH
PhCH2
H2C—CH=CH2
H2C—C≡CH
Ph
CMe3
CMe3
PhCH2
H
Me
7d
H2C—CH=CH2
7h
7l
CMe3 H2C—C≡CH

1506
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Lichitsky et al.
Scheme 3
Table 1. Yields, melting points, and elemental analysis data for compounds 7a—l
Comꢀ
pound
Substituents
M.p.
/°C
Yield
(%)
Found
Calculated
Molecular
formula
(%)
R´
R″
С
H
N
7a
7b
7c
7d
7e
7f
Н
H
H
Me
>300
decomp.
>300
decomp.
261—262
60
50
51
59
54
60
65
57
71
72
65
78
61.71
61.41
62.49
62.68
64.01
63.82
65.11
65.30
65.58
65.75
69.95
69.76
71.52
71.34
71.52
71.73
74.45
74.27
65.94
65.79
66.39
66.65
67.12
68.95
3.89
3.96
4.60
4.51
4.93
5.00
4.86
4.79
4.07
4.14
4.77
4.68
4.98
4.90
4.30
4.38
4.69
4.79
5.79
5.85
6.30
6.21
5.70
5.79
22.18
22.04
21.04
20.88
20.01
19.85
19.15
19.04
19.30
19.17
16.42
16.27
15.29
15.13
15.35
15.21
13.21
13.32
18.16
18.05
17.39
17.27
16.21
16.08
C13H10N4O2
C14H12N4O2
C15H14N4O2
C16H14N4O2
C16H12N4O2
C20H16N4O2
C22H18N4O2
C22H16N4O2
C26H20N4O2
C17H18N4O2
C18H20N4O2
C20H20N4O2
H
Et
H
H2C—CH=CH2
H2C—C≡CH
PhCH2
>300
H
297—298
169—170
149—151
147—149
129—130
H
7g
7h
7i
Ph
H2C—CH=CH2
H2C—C≡CH
PhCH2
Ph
Ph
7j
СMe3
СMe3
СMe3
H
>270
decomp.
205—207
7k
7l
Me
H2C—C≡CH
211—212

Synthesis of a spirooxoindole system
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1507
Table 2. 1H NMR spectra for compounds 7a—l (DMSOꢀd6, δ, J/Hz)
Comꢀ
pound
R´
R″
H—C—H
H—C—H
Arisatin
CHpyrazol
NH
(br.s, 1 H)
(d, 1 H, J = 16)
7a
12.18 (br.s, 1 H)
10.53 (br.s, 1 H, NH)
2.84
2.89
2.49
6.88—7.26 (m, 5 H)
7.04—7.36 (m, 5 H)
10.47
10.56
7b
7c
12.19 (br.s, 1 H)
12.19 (br.s, 1 H)
3.13 (s, 3 H, Me)
2.45*
1.15 (t, 3 H, Me, J = 7);
3.68 (q, 2 H, CH2, J = 7)
4.29 (s, 2 H, CH2);
5.13 (m, 2 H, CH2);
5.87 (m, 1 H, СH)
3.36 (s, 1 H, CH);
4.50 (s, 2 H, CH2)
4.88 (s, 2 H, CH2);
6.93—7.36 (m, 10 H, Ph)
4.32 (s, 2 H, CH2);
5.16 (m, 2 H, CH2);
5.88 (m, 1 H, СH)
3.31 (s, 1 H, CH);
2.89
2.95
2.45
2.48
7.05—7.35 (m, 5 H)
6.98—7.32 (m, 5 H)
10.55
10.57
7d
12.21 (br.s, 1 H)
7e
7f
12.23 (br.s, 1 H)
12.23 (br.s, 1 H))
2.97
2.99
3.16
2.42
2.52
2.63
7.08—7.39
(m, 4 H)
7.02
(s, 1 H)
10.58
10.60
10.86
6.93—7.36 (m, 10 H)
7g
7.03—7.55
(m, 5 H, Ph)
7.03—7.55
(m, 4 H)
6.97
(s, 1 H)
7h
7i
7.12—7.57
(m, 5 H, Ph)
6.99—7.59
3.18
2.57
7.12—7.57
(m, 4 H)
6.93
(s, 1 H)
10.87
4.54 (s, 2 H, CH2)
4.93 (s, 2 H, CH2);
6.99—7.59 (m, 5 H, Ph)
(m, 5 H, Ph)
3.19
2.95
2.99
3.07
2.67
2.51
2.51
2.48
6.99—7.59
(m, 4 H)
6.86—7.26
(m, 4 H)
7.04—7.37
(m, 4 H)
7.09—7.40
(m, 4 H)
6.98
(s, 1 H)
6.62
(s, 1 H)
6.58
(s, 1 H)
6.56
(s, 1 H)
10.90
10.33
10.37
10.42
7j
1.56 (s, 9 H, CMe)
10.48 (br.s, 1 H, NH)
7k
7l
1.56 (s, 9 H, CMe3) 3.13 (s, 3 Н, Me)
1.56 (s, 9 H, CMe3) 3.28 (s, 1 H, CH);
4.51 (s, 2 H, CH2)
* J = 16.7 Hz.
residue. The precipitate that formed was filtered off and recrysꢀ
talized from acetone.
threeꢀcomponent process because of the instability of the
oxoindolylidene derivatives of Meldrum´s acid.
Synthesis of compounds 7g,h,l (method B). The reaction mixꢀ
ture was poured in water (100 mL), the precipitate that formed
was filtered off and recrystalized from diethyl ether.
Synthesis of compounds 7i—k (method C). The reaction mixꢀ
ture was concentrated in vacuo, the residue was recrystallized
from ethanol, filtered off, and washed with ethanol and water.
Experimental
The 1H NMR spectra were recorded on a Bruker Avance II
300 spectrometer (300.00 MHz) in DMSOꢀd6. The melting
points were determined on a Boetius hotꢀstage apparatus and are
uncorrected. The course of reactions and the purity of the
obtained compounds were monitored by TLC (Silica gel 60 F254
(Merck), ethyl acetate—hexane, 3 : 1).
Synthesis of the starting esters18,19 and alkylisatin deꢀ
rivatives20—22 was carried out according to the described
methods.
Synthesis of 1,7ꢀdihydrospiro[pyrazolo[3,4ꢀb]pyridineꢀ4,3´ꢀ
indole]ꢀ2´,6(1´H,5H)ꢀdiones (7a—l). A mixture of ester 12
(2 mmol) and NaOH (0.16 g, 4 mmol) in ethanol (5 mL) and
water (5 mL) was refluxed for 4 h and concentrated to dryness.
Meldrum´s acid (0.32 g, 2.3 mmol), the corresponding isatin
(2.15 mmol), and acetic acid (7 mL) were added to the residue.
The obtained mixture was refluxed for 6 h. Subsequent workꢀup
of the reaction mixture was carried out according to one of the
methods mentioned below.
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Received February 18, 2009