Three-component condensation of 3-aminothiophene derivatives with isatines and Meldrum's acid. Synthesis of 2,5′-dioxo-3′-phenyl-5′, 6′-dihydro-4′H-spiro[indoline-3,7′-thieno[3,2-b]pyridine] -2′-carboxylic acids

Article abstract of DOI:10.1007/s11172-013-0136-8

A method for the synthesis of 2,5′-dioxo-3′-phenyl-5′, 6′-dihydro-4′H-spiro[indoline-3,7′-thieno[3,2-b]pyridine] -2′-carboxylic acids was elaborated based on the three-component condensation of 3-aminothiophenes, Meldrum's acid, and isatines.

Full text of DOI:10.1007/s11172-013-0136-8

Russian Chemical Bulletin, International Edition, Vol. 62, No. 4, pp. 1026—1031, April, 2013
1026
Threeꢀcomponent condensation of 3ꢀaminothiophene derivatives
with isatines and Meldrum´s acid.
Synthesis of 2,5´ꢀdioxoꢀ3´ꢀphenylꢀ5´,6´ꢀdihydroꢀ4´Hꢀspiro[indolineꢀ3,7´ꢀ
thieno[3,2ꢀb]pyridine]ꢀ2´ꢀcarboxylic acids*
B. V. Lichitsky, R. M. Belyi, 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 method for the synthesis of 2,5´ꢀdioxoꢀ3´ꢀphenylꢀ5´,6´ꢀdihydroꢀ4´Hꢀspiro[indolineꢀ3,7´ꢀ
thieno[3,2ꢀb]pyridine]ꢀ2´ꢀcarboxylic acids was elaborated based on the threeꢀcomponent conꢀ
densation of 3ꢀaminothiophenes, Meldrum´s acid, and isatines.
Key words: threeꢀcomponent condensation, Meldrum´s acid, 2,5´ꢀdioxoꢀ3´ꢀphenylꢀ5´,6´ꢀ
dihydroꢀ4´Hꢀspiro[indolineꢀ3,7´ꢀthieno[3,2ꢀb]pyridine]ꢀ2´ꢀcarboxylic acids, 3ꢀaminothioꢀ
phenes, decarboxylation, isatines.
Earlier,1–9 we have developed a general approach to
the synthesis of substituted fused dihydropyridinꢀ2ꢀone
systems based on the threeꢀcomponent condensation of
labile heterocyclic amines with Meldrum´s acid and carboꢀ
nyl compounds. As the starting compounds for the synꢀ
thesis of labile amines, we used vicinal aminocarboxylic
acids prepared by the alkali hydrolysis of the correspondꢀ
ing esters or stable hydrochlorides neutralized by anꢀ
hydrous sodium acetate.
formed in situ, aromatic aldehydes 3, and Meldrum´s acid 4
(Scheme 1).
Further, we extended this approach to more stable
3ꢀaminothiophene derivatives, that made it possible to
obtain the earlier unknown 6,7ꢀdihydroꢀ4Hꢀthieno[3,2ꢀb]ꢀ
pyridinꢀ5ꢀones 5 (see Ref. 2) in good yields (Scheme 2).
The method suggested was illustrated by the synthesis
of fused dihydropyridinone systems 6 (see Ref. 3) from
3ꢀaminopyrrole derivatives (Scheme 3), as well as the inꢀ
volvement of 4ꢀaminothiazole4 and 4ꢀaminoselenꢀ
azole5 derivatives in the threeꢀcomponent condensation
(Scheme 4).
This method for the first time was used for the prepaꢀ
ration of substituted 4,7ꢀdihydroꢀ5Hꢀthieno[2,3ꢀb]pyridꢀ
inꢀ6ꢀones 1 (see Ref. 1) based on 2ꢀaminothiophenes 2
Scheme 1
* Dedicated to Academician of the Russian Academy of Sciences I. P. Beletskaya on the occasion of her anniversary.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 1025—1030, April, 2013.
1066ꢀ5285/13/6204ꢀ1026 © 2013 Springer Science+Business Media, Inc.

Threeꢀcomponent condensation of 3ꢀaminothiophenes
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1027
Scheme 2
Scheme 3
Scheme 4
X = S, Se
Note that we had to change the reaction conditions
developed earlier in the synthesis of dihydrothiazoloꢀ
[4,5ꢀb]pyridinꢀ5ꢀone derivatives 7 and dihydroselenazoloꢀ
[4,5ꢀb]pyridinꢀ5ꢀone derivatives 8, since the use of acetic
acid as the solvent led to the deep resinification of the
reaction mixture, that was apparently due to the lability of
the imino forms.
the fused products. We successfully synthesized 6,7ꢀdiꢀ
hydroꢀ4Hꢀthiazolo[4,5ꢀb]pyridinꢀ5ꢀones 9 in good yields
(see Ref. 6) from esters 10, using the sequence of converꢀ
sions given in Scheme 5.
We also obtained new 6,7ꢀdihydroꢀ4Hꢀisothiazoloꢀ
[4,5ꢀb]pyridinꢀ5ꢀones 11 (see Ref. 7) by the threeꢀcomꢀ
ponent condensation of 4ꢀaminoisothiazole derivatives
formed in situ from the corresponding hydrochlorides 12
with aromatic aldehydes and Meldrum´s acid (Scheme 6).
The presence of the secondary amino group at position
2 of the thiazole ring did not interfere with the synthesis of
Scheme 5

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Lichitsky et al.
Scheme 6
[3,4ꢀb]pyridineꢀ4,3´ꢀindole]ꢀ2´,6(1´H,5H)ꢀdiones 16 in
good yields (Scheme 8).
Scheme 8
Note that the synthesis of the target compounds was
usually accomplished by the reflux of components in aceꢀ
tic acid. The 5ꢀaminoimidazole derivatives, in contrast
to the heterocycles considered earlier, are extremely
unstable in the free state, and it is impossible to use conꢀ
ditions developed for other system in this case: the reflux
in acetic acid leads to the resinification of the reaction
mixture and a sharp drop in the yield of the target comꢀ
pounds. The use of milder conditions for the heteroꢀ
cyclization made it possible to avoid destruction of the
free aminoimidazole: carrying out the reaction in acetic
acid at room temperature for 24 h led to the earlier
unknown imidazopyridinones 13.8 Sodium salts 14 obꢀ
tained by the alkali hydrolysis of esters 15 were used as the
starting compounds for the preparation of free amines
(Scheme 7).
Scheme 7
The purpose of the present work was to synthesize earꢀ
lier unknown substituted 2,5´ꢀdioxoꢀ3´ꢀphenylꢀ5´,6´ꢀdiꢀ
hydroꢀ4´Hꢀspiro[indolineꢀ3,7´ꢀthieno[3,2ꢀb]pyridine]ꢀ
2´ꢀcarboxylic acids 17 using a threeꢀcomponent condenꢀ
sation of 3ꢀaminothiophene derivatives 18, isatines 19,
and Meldrum´s acid 4. We showed that the reaction of
these reagents led to the formation of products 17 in good
yields. The acids 20 necessary for the synthesis, which
underwent selective decarboxylation leading to the formaꢀ
tion of 3ꢀaminothiophene derivatives 18, were obtained as
sodium salts 21 by the alkali hydrolysis of the correspondꢀ
ing esters 22 (Scheme 9).
It should be noted that the threeꢀcomponent condenꢀ
sation used aldehydes in all the cases considered above. At
the same time, it is obvious that involvement of ketones in
this process will considerably broaden the structures of the
reaction products. However, it appeared that the condenꢀ
sation with ketones under conditions developed earlier did
not lead to the target compounds, giving rather a complex
mixture of products. It could have been suggested that the
use of activated ketones close to aldehydes in their reactivꢀ
ity, for example, isatines, would lead to the fused spiro
systems containing an indolone fragment, capable of furꢀ
ther modifications. In fact, we found9 that the reaction of
5ꢀaminopyrazole derivatives with isatines and Meldrum´s
acid led to the formation of 1,7ꢀdihydrospiro[pyrazoloꢀ
3ꢀAminothiophenes are labile compounds10 and can
be obtained by decarboxylation11 of vicinal amino acids.
The acids themselves are formed by the alkali hydrolysis of
the corresponding esters.11 In our work, amino acids 18
were generated in situ from the preliminary obtained soꢀ
dium salts 21. The latter were formed by the alkali hydroꢀ
lysis of esters 22 and involved in the threeꢀcomponent
condensation without additional purification.
We suggest that initially, most likely, isatine 19 adds to
Meldrum´s acid 4 with the formation of the oxoindolꢀ
ylidene derivative of Meldrum´s acid 23, which further
reacts with aminothiophene 18 to give unstable interꢀ
mediate compound 24, which transforms to the final prodꢀ
uct with elimination of CO2 and acetone (pathway A)

Threeꢀcomponent condensation of 3ꢀaminothiophenes
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1029
Scheme 9
17, 19: R = H, R´ = H (a); R = Me, R´ = H (b); R = CH2Ph, R´ = H (c); R = CH2CO2Et, R´ = H (d); R = H; R´ = Me (e)
(Scheme 10). An alternative scheme of the process (pathꢀ
way B) includes the addition of Meldrum´s acid 4 to
the Michael adduct 25 and subsequent intramolecular
cyclization.
It is necessary to note that in contrast to the methods
described earlier for the synthesis involving aromatic aldeꢀ
hydes, the condensation of Meldrum´s acid and isatine
does not give stable oxoindolylidene derivative 23, which
could have been isolated in the free form. Therefore, the
approaches described earlier in the literature for Meldrum´s
acid arylmethylidene derivatives and stable heterocyclic
enamines12—14 cannot be used in the case under considerꢀ
ation. The synthesis of the target products 19 was in fact
successful under conditions of the threeꢀcomponent conꢀ
Scheme 10

1030
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
Lichitsky et al.
1ꢀBenzylꢀ2,5´ꢀdioxoꢀ3´ꢀphenylꢀ5´,6´ꢀdihydroꢀ4´Hꢀspiroꢀ
[indolineꢀ3,7´ꢀthieno[3,2ꢀb]pyridine]ꢀ2´ꢀcarboxylic acid (17c).
The yield was 75%, m.p. > 320 C. 1H NMR, : 2.78 (d, 1 H,
H—C—H (CH2CO); J = 16 Hz); 3.33 (d, 1 H, H—C—H
(CH2CO), J = 16 Hz); 4.87 (d, 1 H, H—C—H (Bn), J = 16 Hz);
5.00 (d, 1 H, H—C—H (Bn), J = 16 Hz); 6.97—7.55 (m, 14 H,
HAr); 9.41 (s, 1 H, NH); 12.83 (br.s, 1 H, COOH). Found (%):
C, 65.21; H, 4.02; N, 7.09; S, 7.98. C15H17N3O2S. Calculatꢀ
ed (%): C, 65.33; H, 3.99; N, 6.93; S, 7.93.
1ꢀ(2ꢀEthoxyꢀ2ꢀoxoethyl)ꢀ2,5´ꢀdioxoꢀ3´ꢀphenylꢀ5´,6´ꢀdiꢀ
hydroꢀ4´Hꢀspiro[indolineꢀ3,7´ꢀthieno[3,2ꢀb]pyridine]ꢀ2´ꢀcarbꢀ
oxylic acid (17d). The yield was 73%, m.p. 262—264 C. 1H
NMR, : 1.20 (t, 3 H, CH3(Et), J = 7 Hz); 2.67 (d, 1 H, H—C—H,
J = 17 Hz); 3.30 (d, 1 H, H—C—H, J = 17 Hz); 4.16 (q, 2 H,
CH2(Et), J = 7 Hz); 4.56 (d, 1 H, H—C—H (NCH2), J = 18 Hz);
4.66 (d, 1 H, H—C—H (NCH2), J = 18 Hz); 7.08—7.55 (m, 9 H,
HAr); 9.42 (s, 1 H, NH); 12.86 (br.s, 1 H, COOH). 13C NMR,
: 13.94, 39.33, 41.20, 48.13, 61.23, 109.46, 121.16, 123.39,
124.13, 127.98, 128.09, 129.60, 129.71, 130.03, 132.06, 133.01,
136.90, 138.72, 142.12, 162.09, 165.42, 167.53, 175.64. Found (%):
C, 56.89; H, 4.07; N, 7.07; S, 7.92. C15H17N3O2S. Calculatꢀ
ed (%): C, 56.99; H, 4.03; N, 7.00; S, 8.01.
densation of 3ꢀaminothiophene derivatives 18, isatines 19,
and Meldrum´s acid 4.
In conclusion, we have developed a new convenient
method for the synthesis of the earlier unknown substitutꢀ
ed 2,5´ꢀdioxoꢀ3´ꢀphenylꢀ5´,6´ꢀdihydroꢀ4´Hꢀspiro[indolꢀ
ineꢀ3,7´ꢀthieno[3,2ꢀb]pyridine]ꢀ2´ꢀcarboxylic acids based
on the threeꢀcomponent condensation of 3ꢀaminothioꢀ
phenes, Meldrum´s acid, and isatine. 3ꢀAminothiophenes
are readily formed in situ by the acidꢀpromoted decarbꢀ
oxylation of 3ꢀaminoꢀ2ꢀthiophenecarboxylic acids, sodiꢀ
um salts of the latter were obtained by the alkali hydrolysis
of available corresponding esters. We showed that the
reaction can be carried out only in the threeꢀcomponent
version, since the Meldrum´s acid oxoindolylidene derivꢀ
atives are unstable.
Experimental
1
H NMR spectra were recorded on a Bruker Avance II 300
spectrometer (300 MHz) in DMSOꢀd6. Melting points were
measured on a Boetius heating stage and were not corrected.
Reactants and solvents used in the work were commercially availꢀ
able from Acros Organics and used without additional purifiꢀ
cation.
Substituted isatines 19b,15 19c,16 19d,17 and 19e18 and diꢀ
methyl 3ꢀaminoꢀ4ꢀphenylthiopheneꢀ2,5ꢀdicarboxylate 222
were obtained according to the procedures described in the litꢀ
erature.
Synthesis of 2,5´ꢀdioxoꢀ3´ꢀphenylꢀ5´,6´ꢀdihydroꢀ4´Hꢀspiroꢀ
[indolineꢀ3,7´ꢀthieno[3,2ꢀb]pyridine]ꢀ2´ꢀcarboxylic acids (18a—e)
(general procedure). A mixture of ester 22 (2 mmol) and NaOH
(0.24 g, 6 mmol) in ethanol (5 mL) and water (5 mL) was reꢀ
fluxed for 4 h and concentrated to dryness. Then, Meldrum´s
acid (0.32 g, 2.3 mol), the corresponding isatine (2.15 mmol),
and acetic acid (7 mL) were added to the residue obtained. The
reaction mixture was refluxed for 45 min and concentratꢀ
ed in vacuo. A precipitate formed was recrystallized from
ethanol with the addition of concentrated hydrochloric acid
(0.7 g), filtered off, and washed with ethanol and water on
the filter.
5ꢀMethylꢀ2,5´ꢀdioxoꢀ3´ꢀphenylꢀ5´,6´ꢀdihydroꢀ4´Hꢀspiroꢀ
[indolineꢀ3,7´ꢀthieno[3,2ꢀb]pyridine]ꢀ2´ꢀcarboxylic acid (17e).
The yield was 82%, m.p. > 320 C. 1H NMR, : 2.27 (s, 3 H,
Me); 2.68 (d, 1 H, H—C—H, J = 16 Hz); 3.16 (d, 1 H, H—C—H,
J = 16 Hz); 6.74—7.79 (m, 8 H, HAr); 9.28 (s, 1 H, NHCO);
10.60 (s, 1 H, NHisatine); 12.80 (br.s, 1 H, COOH). 13C NMR,
: 20.65, 38.30, 48.73, 109.86, 122.00, 124.66, 127.96, 128.02,
129.69, 131.13, 131.26, 131.49, 132.11, 136.72, 136.88, 138.42,
139.09, 162.11, 167.80, 177.12. Found (%): C, 58.65; H, 3.71;
N, 8.57; S, 9.64. C16H12N2O4S. Calculated (%): C, 58.53;
H, 3.68; N, 8.53; S, 9.77.
References
1. B. V. Lichitsky, A. N. Komogortsev, A. A. Dudinov, M. M.
Krayushkin, Russ. Chem. Bull. (Int. Ed.), 2008, 57, 2175 [Izv.
Akad. Nauk, Ser. Khim., 2008, 2133].
2. B. V. Lichitsky, R. M. Belyi, A. N. Komogortsev, A. A.
Dudinov, M. M. Krayushkin, Russ. Chem. Bull. (Int. Ed.),
2009, 58, 387 [Izv. Akad. Nauk, Ser. Khim., 2009, 382].
3. B. V. Lichitsky, A. A. Dudinov, A. N. Komogortsev, M. M.
Krayushkin, Mendeleev Commun., 2010, 20, 255.
4. A. A. Dudinov, B. V. Lichitsky, I. A. Antonov, A. N. Komoꢀ
gortsev, P. A. Belyakov, M. M. Krayushkin, Russ. Chem.
Bull. (Int. Ed.), 2008, 57, 1740 [Izv. Akad. Nauk, Ser. Khim.,
2008, 1707].
5. A. A. Dudinov, A. N. Komogortsev, B. V. Lichitsky,
M. M. Krayushkin, Phosphorus, Sulfur, Silicon, 2010,
185, 1230.
6. A. A. Dudinov, B. V. Lichitsky, A. N. Komogortsev, M. M.
Krayushkin, Mendeleev Commun., 2009, 19, 87.
7. B. V. Lichitsky, A. N. Komogortsev, R. M. Belyi,
A. A. Dudinov, M. M. Krayushkin, Russ. Chem. Bull.
(Int. Ed.), 2009, 58, 1538 [Izv. Akad. Nauk, Ser. Khim.,
2009, 1493].
2,5´ꢀDioxoꢀ3´ꢀphenylꢀ5´,6´ꢀdihydroꢀ4´Hꢀspiro[indolineꢀ
3,7´ꢀthieno[3,2ꢀb]pyridine]ꢀ2´ꢀcarboxylic acid (17a). The yield
1
was 78%, m.p. > 320 C. H NMR, : 2.69 (d, 1 H, H—C—H,
J = 16 Hz); 3.22 (d, 1 H, H—C—H, J = 16 Hz); 6.84—7.62
(m, 9 H, HAr); 9.30 (s, 1 H, NHCO); 10.69 (s, 1 H, NHisatine);
12.80 (br.s, 1 H, COOH). 13C NMR, : 39.18, 48.69, 110.10,
122.45, 124.21, 127.96, 128.51, 128.92, 129.50, 129.67, 131.13,
132.10, 132.64, 136.89, 138.45, 141.62, 162.08, 167.77, 177.13.
Found (%): C, 57.41; H, 3.25; N, 8.84; S, 10.15. C15H10N2O4S.
Calculated (%): C, 57.32; H, 3.21; N, 8.91; S, 10.20.
1ꢀMethylꢀ2,5´ꢀdioxoꢀ3´ꢀphenylꢀ5´,6´ꢀdihydroꢀ4´Hꢀspiroꢀ
[indolineꢀ3,7´ꢀthieno[3,2ꢀb]pyridine]ꢀ2´ꢀcarboxylic acid (17b).
The yield was 71%, m.p. > 320 C. 1H NMR, : 1.90 (s, 3 H,
Me); 2.69 (d, 1 H, H—C—H, J = 16 Hz); 3.25 (d, 1 H, H—C—H,
J = 16 Hz); 6.04—7.57 (m, 9 H, HAr); 9.31 (s, 1 H, NH); 12.42
(br.s, 1 H, COOH). Found (%): C, 58.64; H, 3.71; N, 8.47;
S, 9.70. C16H12N2O4S. Calculated (%): C, 58.53; H, 3.68;
N, 8.53; S, 9.77.
8. B. V. Lichitsky, A. N. Komogortsev, A. A. Dudinov, M. M.
Krayushkin, Russ. Chem. Bull. (Int. Ed.), 2012, 63, No. 8
[Izv. Akad. Nauk, Ser. Khim., 2012, 1575].

Threeꢀcomponent condensation of 3ꢀaminothiophenes
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 4, April, 2013
1031
9. B. V. Lichitsky, A. N. Komogortsev, A. A. Dudinov, M. M.
Krayushkin, Russ. Chem. Bull. (Int. Ed.), 2009, 58, 1504 [Izv.
Akad. Nauk, Ser. Khim., 2009, 1460].
10. S. Gronowitz, Adv. Helerocycl. Chem. 1963, 1,1.
11. G. Kirsch, D. Cagniat, P. Cagniat, J. Heterocycl. Chem.,
15. S. J. Garden, J. C. Torres, L. E. da Silva, A. C. Pinto, Synꢀ
thetic Commun., 1998, 28, 1679.
16. J. Azizian, H. FallahꢀBagherꢀShaidaei, H. Kefayati, Synꢀ
thetic Commun., 2003, 33, 789.
17. O. M. Radul, G. I. Zhungietu, M. A. Rekhter, S. M. Bukhaꢀ
nyuk, Chem. Heterocyclic Comp., 1983, 19, 286.
18. M. G. Bursavich, A. M. Gilbert, S. Lombardi, K. E. Georꢀ
giadis, E. Reifenberg, C. R Flannery, E. A. Morris, Bioorg.
Med. Chem. Lett., 2007, 17, 5630.
1982, 19, 443
12. J. Quiroga, A. Hormaza, B. Insuasty, J. Heterocycl. Chem.,
1998, 35, 409.
13. B. Pita, E. Sotelo, M. Suarez, E. Ravina, E. Ochoa, Y. Verꢀ
decia, H. Novoa, N. Blaton, C. de Ranter, O. M. Peeters,
Tetrahedron, 2000, 56, 2473.
14. R. Rodriguez, M. Suarez, E. Ochoa, N. Martin, M. Quinꢀ
teiro, C. Seoane, J. L. Soto, J. Heterocycl. Chem., 1996,
33, 45.
Received December 19, 2012;
in revised form February 27, 2013