Domino-reactions of isatins with 5-aminopyrazoles and 2,2-dimethyl-1,3-dioxane-4,6-dione

Authors

  • N. I. Zemlyana State Institution “V. J. Danilevsky Institute of Problems of Endocrine Pathology at the Academy of Medical Sciences of Ukraine, Ukraine
  • T. M. Karnozhitska State Institution “V. J. Danilevsky Institute of Problems of Endocrine Pathology at the Academy of Medical Sciences of Ukraine, Ukraine
  • T. L. Pavlovska State Scientific Institution “Institute for Single Crystals” of National Academy of Sciences of Ukraine; V. N. Karazin Kharkiv National University, Ukraine
  • O. V. Mazepa O. Bogatsky Physico-Chemical Institute of the National Academy of Sciences of Ukraine, Ukraine
  • V. I. Musatov State Scientific Institution “Institute for Single Crystals” of National Academy of Sciences of Ukraine, Ukraine
  • V. V. Lipson State Institution “V. J. Danilevsky Institute of Problems of Endocrine Pathology at the Academy of Medical Sciences of Ukraine; V. N. Karazin Kharkiv National University, Ukraine

DOI:

https://doi.org/10.24959/ophcj.18.950

Keywords:

pyrazolo[3, 4-b]pyridine-4-spiroindolinones, 3-(5-aminopyrazol-4-yl)-3-hydroxy-2-oxindolines, isatins, 5-aminopyrazoles, 2, 2-dimethyl-1, 3-dioxane-4, 6-dione, domino-reactions

Abstract

Aim. To determine the direction of the interaction of isatins with 5-amino-pyrazoles and 2,2-dimethyl-1,3-dioxane-4,6-dione under different conditions.

Results and discussion. The domino-reactions of isatins, 5-aminopyrazoles and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid) in the alcoholic medium are completed by formation of a mixture of pyrazolo[3,4-b]pyridine-4-spiroindolinones and 3-(5-aminopyrazol-3-yl)-3-hydroxy-2-oxindolines with the predominant content of spiro compounds. 3-(5-Aminopyrazol-4-yl)-3-hydroxy-2-oxindolines may turn into pyrazolo[3,4-b]pyridine-4-spiroindolinones very slowly only as a result of retrograde fragmentation to isatin and aminopyrazole in the presence of Meldrum’s acid.

Experimental part. The mixtures of pyrazolo[3,4-b]pyridine-4-spiroindolinones and 3-(5-aminopyrazol-3-yl)-3-hydroxy-2-oxindolines separated by crystallization were obtained by boiling in methanol of the equimolar quantity of isatins, 5-aminopyrazoles and Meldrum’s acids. The yield for spiro compounds is 26-82 %, and for 3-(5-aminopyrazole-3-yl)-3-hydroxy-2-oxindolines it is 5-23 %. The transformation of the latter into the spiro compound in the presence of Meldrum’s acid occurs with prolonged boiling in the alcoholic medium and is accompanied with extremely low yields. The structure of all compounds synthesized has been proven by 1H NMR, mass spectra and elemental analysis.

Conclusions. It has been found that in the three-component reactions of isatins, 5-aminopyrazoles and 2,2-dimethyl-1,3-dioxane-4,6-dione there are two competing directions of the interaction of isatin with nucleophiles. One of them is the nucleophilic addition of the C4 reaction center of aminopyrazole to the carbonyl group of isatin, which results in 3-(5-aminopyrazol-4-yl)-3-hydroxy-2-oxidolines. Another one is the Knoevenagel condensation of isatin with dioxane-4,6-dione – a domino process that starts formation of the predominant reaction products – pyrazolo[3,4-b]pyridine-4-spiroindolinones.

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References

  1. Marson, C. M. (2011). New and unusual scaffolds in medicinal chemistry. Chemical Society Review, 40 (11), 5514–5533. https://doi.org/10.1039/c1cs15119c
  2. Pavlovska, T. L., Redkin, R. G., Lipson, V. V., & Atamanuk, D. V. (2015). Molecular diversity of spirooxindoles. Synthesis and biological activity. Molecular Diversity, 20 (1), 299–344. https://doi.org/10.1007/s11030-015-9629-8
  3. Singh, G. S., & Desta, Z. Y. (2012). Isatins As Privileged Molecules in Design and Synthesis of Spiro–Fused Cyclic Frameworks. Chemical Reviews, 112 (11), 6104–6155. https://doi.org/10.1021/cr300135y
  4. Ghahremanzadeh, R., Imani Shakibaei, G., Ahadi, S., & Bazgir, A. (2010). One–Pot, Pseudo Four–Component Synthesis of a Spiro[diindeno[1,2–b:2’,1’–e]pyridine–11,3’–indoline]–trione Library. Journal of Combinatorial Chemistry, 12 (1), 191–194. https://doi.org/10.1021/cc900130a
  5. Ghahremanzadeh, R., Sayyafi, M., Ahadi, S., & Bazgir, A. (2009). Novel One–Pot, Three–Component Synthesis of Spiro[Indoline–pyrazolo[4’,3’:5,6]pyrido[2,3–d]pyrimidine]trione Library. Journal of Combinatorial Chemistry, 11 (3), 393–396. https://doi.org/10.1021/cc8001958
  6. Jadidi, K., Ghahremanzadeh, R., & Bazgir, A. (2009). Efficient Synthesis of Spiro[chromeno[2,3–d]pyrimidine–5,3’–indoline]–tetraones by a One–Pot and Three–Component Reaction. Journal of Combinatorial Chemistry, 11 (3), 341–344. https://doi.org/10.1021/cc800167h
  7. Shakibaei, G. I., Samadi, S., Ghahremanzadeh, R., & Bazgir, A. (2010). Simple and Catalyst–Free Synthesis of Oxoindolin–3–yl Phosphonates. Journal of Combinatorial Chemistry, 12(2), 295–297. https://doi.org/10.1021/cc900169p
  8. Shakibaei, G., Feiz, A., Reza Khavasi, H., Abolhasani Soorki, A., & Bazgir, A. (2010). Simple Three–Component Method for the Synthesis of Spiroindeno[1,2–b]pyrido[2,3–d]pyrimidine–5,3’–indolines. ACS Combinatorial Science, 13 (1), 96–99. https://doi.org/10.1021/co1000053
  9. Shakibaei, G., Feiz, A., & Bazgir, A. (2011). A simple and catalyst–free three–component method for the synthesis of spiro[indenopyrazolopyridine indoline]diones and spiro[indenopyridopyrimidine indoline]triones. Comptes Rendus Chimie, 14 (6), 556–562. https://doi.org/10.1016/j.crci.2010.10.001
  10. Anwar, H. F., Elnagdi M. H. (2009). Recent developments in aminopyrazole chemistry / H. F. Anwar, M. H. Elnagdi // ARKIVOC, Part (i), 198–250. https://doi.org/10.3998/ark.5550190.0010.107
  11. Jachak, M. N., Avhale, A. B., Medhane, V. J., & Toche, R. B. (2006). A convenient route for the synthesis of pyrazolo[3,4–d]pyrimidine, pyrazolo[3,4–b][1,6]naphthyridine and pyrazolo[3,4–b]quinoline derivatives. Journal of Heterocyclic Chemistry, 43 (5), 1169–1175. https://doi.org/10.1002/jhet.5570430506
  12. Quiroga, J., Portillo, S., Pérez, A., Gálvez, J., Abonia, R., & Insuasty, B. (2011). An efficient synthesis of pyrazolo[3,4–b]pyridine–4–spiroindolinones by a three–component reaction of 5–aminopyrazoles, isatin, and cyclic β–diketones. Tetrahedron Letters, 52 (21), 2664–2666. https://doi.org/10.1016/j.tetlet.2011.03.067
  13. Lipson, V. V., Borodina, V. V., Shirobokova, M. G., Desenko, S. M., Shishkin, O. V., Zubatuk, R. I. (2007). Chemistry of Heterocyclic Compounds, 43(4), 490–495.
  14. Lipson, V. V., Shirobokova, M. G., Musatov, V. I. (2005). Zhurnal orhanichnoi ta farmatseevtychnoi khimii, 3 (3), 64 – 69.
  15. Pushechnikov, A. O., Volochnyuk, D. M., & Tolmachev, A. A. (2002). Interaction of Izatins with Some Five–membered Aminoheterocycles. Synlett, 2002 (07), 1140–1142. https://doi.org/10.1055/s-2002-32573

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Published

2018-12-14

How to Cite

(1)
Zemlyana, N. I.; Karnozhitska, T. M.; Pavlovska, T. L.; Mazepa, O. V.; Musatov, V. I.; Lipson, V. V. Domino-Reactions of Isatins With 5-Aminopyrazoles and 2,2-Dimethyl-1,3-Dioxane-4,6-Dione. J. Org. Pharm. Chem. 2018, 16, 3-10.

Issue

Vol. 16 No. 4(64) (2018)

Section

Original Researches

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