For citation:
Borisova S. V., Sorokin V. V., Klochkova I. N. Synthesis of spiropyrrolizidines containing quinoxaline and pyrrole fragments. Izvestiya of Saratov University. Chemistry. Biology. Ecology, 2023, vol. 23, iss. 2, pp. 175-184. DOI: 10.18500/1816-9775-2023-23-2-175-184, EDN: CSZNTZ
Synthesis of spiropyrrolizidines containing quinoxaline and pyrrole fragments
The reaction of 1,3-dipolar cycloaddition azomethine ylides obtained by the in situ interaction of 11H-indeno[1,2-b]quinoxalin-11-one and proline, and 3-phenyl-1-pyrrolyl-2-en-1-ones has been used for the synthesis of substituted spiropyrrolizidines in continuation of the study the use of new enones as dipolarophiles. The conditions for the implementation of a three-component synthesis (temperature regime, solvent, activation method) are selected. The best performance has been obtained by refl uxing the reaction mixture in ethanol. Ultrasonic activation did not reduce the reaction time or increase the yields signifi cantly. The reaction proceeds regio- and diastereoselectively with the formation of a single type of products in 72–76% yields. It has been found that carrying out the process in the mode of a four-component reaction using ninhydrin and 1,2-phenylphamine, the reaction product of which is 11H-indeno[1,2-b]quinoxalin-11-one, with the selected dipolarophile is impossible due to the formation of ninhydrin azomethine ylide and proline and its interaction with a dipolarophile to give substituted spiro[indene-2,3’- pyrrolysine]-1,3-diones, which has been proven by a counter synthesis using enone, ninhydrin and proline, which also results in the same type products with yields of 89–92%. A probable scheme of the studied transformations is proposed. Regio- and diastereoselectivity testifi es in favor of concerted cycloaddition, passing in both cases through a transition state in which a bond is formed between the most electrophilic β-carbon atom of the enone system and the nucleophilic carbon atom of the dipole. The reasons for the observed features are discussed. The composition and structure of the fi nal products have been confi rmed by elemental analysis, 1 Н, 13С NMR, HMBC, NOESY spectroscopy. The resulting compounds contain pharmacophoric quinoxaline and pyrrole fragments and can be used to study various types of biological activity characteristic of structures with similar fragments.
- Zheng T., Tice C. M., Singh S. B The use of spirocyclic scaffolds in drug discovery // Bioorganic Med. Chem. Lett. 2014. Vol. 24. P. 3673–3682. https://doi.org/10.1016/j.bmcl.2014.06.081
- 2. Aldeghi M. Two- and three-dimensional rings in drugs // Chem. Biol. Drug Des. 2014. Vol. 83, № 4. P. 450–461. https://doi.org/10.1111/cbdd.12260
- Tumskiy R. S., Burygin G. L., Anis’kov A. A., Klochkova I. N. Synthesis of novel spirooxindole-pyrrolidines and evaluation of their cytotoxic activity // Pharmacological Reports. 2019. Vol. 71. Р. 357–360. https://doi.org/10.1016/j.pharep.2018.12.004
- Борисова С. В., Сорокин В. В. Синтез полизамещенных спиропирролидинов с использованием 2-ацетилфурана, 2-ацетилтиофена и 2-ацетилпиррола // Известия Саратовского университета. Новая серия. Серия: Химия. Биология. Экология. 2021. Т. 21, вып. 3. С. 254–259. https://doi.org/10.18500/1816-9775-2021-21-3-254-259
- Barkov A. Y., Zimnitskiy N. S., Kutyashev I. B., Korotaev V. Y., Moshkin V. S., Sosnovskikh V. Y. Regio- and stereoselective 1,3-dipolar cycloaddition of indenoquinoxalinone azomethine ylides to β-nitrostyrenes: synthesis of spiro[indeno[1,2-b]quinoxaline-11,3’-pyrrolizidines] and spiro[indeno[1,2-b]quinoxaline-11,2’-pyrrolidines // Chemistry of Heterocyclic Compounds. 2017. Vol. 53, № 4. P. 451–459. https://doi.org/10.1007/s10593-017-2074-0
- Barkov A. Y., Zimnitskiy N. S., Kutyashev I. B., Korotaev V. Y., Moshkin V. S., Sosnovskikh V. Y. Highly regio- and stereoselective 1,3-dipolar cycloaddition of stabilized azomethine ylides to 3,3,3-trihalogeno-1-nitropropenes: Synthesis of trihalomethylated spiroindenepyrroli(zi) dines // Journal of Fluorine Chemistry. 2017. Vol. 204. P. 37–44. https://doi.org/10.1016/j.jfluchem.2017.10.005
- Кутяшев И. Б., Барков А. Ю., Зимницкий Н. С., Коротаев В. Ю., Сосновских В. Я. Различное поведение азометин-илидов на основе 11H-индено[1,2- b] хиноксалин-11-она и пролина/саркозина в реакциях с 3-нитро-2H-хроменами // Химия гетероциклических соединений. 2019. Т. 55, № 9. C. 861–874. https://doi.org/10.1007/s10593-019-02550-1
- Korotaev V. Y., Zimnitskiy N. S., Barkov A. Y., Kutyashev I. B., Sosnovskikh V. Y. Stabilized azomethine ylides derived from indeno[1,2-b]quinoxalinones in [3+2] cycloaddition reactions with electrophilic alkenes // Chem. Heterocycl. Comp. 2018. Vol. 54, № 10. P. 905–922. https://doi.org/10.1007/s10593-018-2369-9
- Singh R., Bhardwaj D., Saini M. R. Recent advancement in the synthesis of diverse spiro-indeno[1,2-b] quinoxalines: A review // RSC Adv. 2021. Vol. 11, № 8. P. 4760–4804. http:/doi.org/10.1039/D0RA09130H
- Reddy M. S., Chowhan L. R., Kumar N. S., Ramesh P., Mukkamala S. B. An expedient regio and diastereoselective synthesis of novel spiropyrrolidinylindenoquinoxalines via 1,3-dipolar cycloaddition reaction // Tetrahedron Letters. 2018. Vol. 59. P. 1366–1371. https:// doi.org/10.1016/j.tetlet.2018.02.044
- Wen R., Cen L., Ma Y., Jing Wang, Zhu S. One-pot fi vecomponent 1,3-dipolar cycloaddition: A facile synthesis of spiropyrrolidine and spiropyrrolizidine derivatives// Tetrahedron Letters. 2018. Vol. 59. P. 1686–1690. https://doi.org/10.1016/j.tetlet.2018.03.059
- Grigg R. The Decarboxylative Route to Azomethine Ylides. Mechanism of 1,3-Dipoie Formation // J. Chem. Soc. Commun. 1987. Vol. 5. P. 49–51. https://doi.org/10.1039/C39870000049
- Filatov A. S., Wang S., Khoroshilova O. V., Lozovskiy S. V., Larina A. G., Boitsov V. M., StepakovA. V. Stereo- and Regioselective 1,3-Dipolar Cycloaddition of the Stable Ninhydrin-Derived Azomethine Ylide to Cyclopropenes: Trapping of Unstable Cyclopropene Dipolarophiles // J. Org. Chem. 2019. Vol. 84, № 11. P. 7017–7036. https://doi.org/10.1021/acs.joc.9b00753
- Arumugam N. A facile ionic liquid-accelerated, fourcomponent cascade reaction protocol for the regioselective synthesis of biologically interesting ferrocene engrafted spiropyrrolidine hybrid heterocycles // J. King Saud Univ. Sci. 2020. Vol. 32, № 4. P. 2500–2504. https://doi.org/10.1016/j.jksus.2020.04.007
- Барков А. Ю., Зимницкий Н. С., Кутяшев И. Б., Коротаев В. Ю., Сосновских В. Я. Неожиданная региохимия в реакции [3+2]-циклоприсоединения азометин-илидов инденохиноксалинонового ряда к арилиденмалононитрилам // Химия гетероциклических соединений. 2018. Т. 54, № 1. C. 43–50.
- Борисова С. В., Сорокин В. В. Синтез новых спироиндолинопирролидинов // Журнал общей химии. 2022. T. 92, № 1. C. 22–30. https://doi.org/10.1134/S1070363222010030