本文发展了一种通过1,3-偶极环加成反应高效合成含硫色烯结构的螺吡咯烷酮吲哚的新方法。在该转化中,(E)-2-苯乙烯基-4H-硫色烯-4-酮作为亲偶极体,而由靛红和L-脯氨酸原位生成的甲亚胺叶立德作为1,3-偶极体。值得注意的是,环加成反应选择性地发生在远离吸电子羰基的γ,δ-双键上,从而保留了共轭的硫色烯酮骨架-这类共轭体系中远端双键参与环加成的例子鲜有报道。该三组分一锅法反应在温和条件下进行,以良好至优异的产率获得了一系列螺环吲哚产物,并具有高度的区域选择性和化学选择性。通过克级实验以及后续的N-酰基化和硫原子选择性氧化为亚砜等衍生化反应,验证了该方法的合成实用性。本工作拓展了螺环吲哚类骨架的化学空间,并为构建具有潜在生物活性的含硫螺环杂环化合物提供了一种实用的合成策略。
A novel and efficient synthesis of thiochromene-containing spiro pyrrolidine oxindoles has been developed via a 1,3-dipolar cycloaddition reaction. In this transformation, (E)-2-styryl-4H-thiochromen-4-one serves as the dipolarophile, while azomethine ylides generated in situ from isatins and L-proline act as the 1,3-dipoles. Notably, the cycloaddition selectively occurs at the γ,δ-double bond remote from the electron-withdrawing carbonyl group, preserving the conjugated thiochromenone framework-a scenario rarely reported in such conjugated systems. The three-component one-pot reaction proceeds under mild conditions to afford a broad range of spirooxindoles in moderate to good yields with high regio- and chemoselectivity. The synthetic utility is demonstrated by a gram-scale experiment and subsequent derivatizations, including N-acylation and selective oxidation of the sulfur atom to the corresponding sulfoxide. This work expands the chemical space of spirooxindole-based scaffolds and provides a practical strategy for constructing sulfur-containing spiro heterocycles with potential bioactivity.
[1] Boddy A. J.; Bull, J. A. Org. Biomol. Chem.2021, 8, 1026.
[2] Liandi A. R.; Cahyana A. H.; Alfariza D. N.; Nuraini R.; Sari R. W.; Wendari, T. P. Green Synth. Catal.2024, 1, 1.
[3] Zhu Y.; Zhang Q.; Fang C.; Zhang Y.; Ma L.; Liu L.; Li Z.; Li F.; Wang J.; Li P.; Zhu W.; Zhang, C. Angew. Chem. Int. Ed.2020, 59, 14065.
[4] Stratmann K.; Moore R. E.; Bonjouklian R.; Deeter J. B.; Patterson G. M. L.; Shaffer S.; Smith C. D.; Smitka, T. A. J. Am. Chem. Soc.1994, 116, 9935.
[5] Cui C. B.; Kakeya H.; Osada H. Tetrahedron1996, 52, 12651.
[6] Nozoye, T.Chem. Pharm. Bull. 1958, 6, 309.
[7] Goudou F.; Petit P.; Moriou C.; Gros O.; Al-Mourabit, A. J. Nat. Prod.2017, 80, 1693.
[8] Palmisano G.; Annunziata R.; Papeo G.; Sisti M. Tetrahedron: Asymmetry1996, 7, 1.
[9] Miyake F. Y.; Yakushijin K.; Horne, D. A. Org. Lett.2004, 6, 711.
[10] Seaton J. C.; Tondeur R.; Marion, L. Can. J. Chem.1958, 36, 1031.
[11] Liu Y.; Wang X.; He L.; Li S.; Zhao, Z. Chin. J. Org. Chem.2024, 44, 1301.
[12] Zhang M.; Sha F.; Wu, X. Y. Chin. J. Org. Chem.2025, 45, 1369.
[13] Nivetha, N.; Venkatesan, J.; Murugan, D.; Rangasamy, L.; Wu, S. P.; Velmathi, S.RSC Adv. 2025, 15, 16623.
[14] Huisgen, R. Angew. Chem. 1960, 72, 595.
[15] Zhao H.; Zhao Y. Molecules2023, 28, 6488.
[16] Antol I.; Štrbac P.; Murata Y.; Margetić, D. Int. J. Mol. Sci.2024, 25, 6524.
[17] Li X.; Yi R.; Liu B.; Li Z.; Yu X.; Yi, P. Chin. J. Org. Chem.2012, 32, 2309.
[18] Wang, H.-K.; Bastow, K. F.; Cosentino, L. M.; Lee, K.-H. J. Med. Chem. 1996, 39, 1975.
[19] Santos C. M. M.; Silva, A. M. S. Chem. Rec.2025, 25, 39.
[20] Jatin; Murugappan S.; Kirad, S.; Ala, C.; Kuthe, P. V.; Kondapalli, C. S. V. G.; Sankaranarayanan, M.0[20] Jatin; Murugappan, S.; Kirad, S.; Ala, C.; Kuthe, P. V.; Kondapalli, C. S. V. G.; Sankaranarayanan, M. RSC Med. Chem. 2025, 16, 1941.
[21] Shen J.; Yang Y.; Hou X.; Zeng W.; Yu A.; Zhao X.; Meng, X. Org. Biomol. Chem.2018, 16, 3487.
[22] Barresi E.; Salerno S.; Marini A. M.; Taliani S.; La Motta C.; Simorini F.; Da Settimo F.; Vullo D.; Supuran, C. T. Bioorg. Med. Chem.2016, 24, 921.
[23] Bang E. J.; Noh S. G.; Ha S.; Jung H. J.; Kim D. H.; Lee A. K.; Hyun M. K.; Kang D.; Lee S.; Park C.; Moon H. R.; Chung H. Y. Molecules2018, 23, 3307.
[24] Zhang Y.; Guo J. M.; Zhang M. M.; Wang R.; Liang C. H.; Zhao Y. M.; Deng Y. Y.; Liu Y. P.; Fu Y. H. Molecules2023, 28, 6050.
[25] Zhang X.; Zhou Q.; Zhou Y.; Wang Z.; Wang J.; Wang M. RSC Adv.2023, 13, 30391.
[26] Xiao L.; Li J.; Chi J.; Yu L.; Li P.; Tang Z.; Tan, S. Phosphorus, Sulfur Silicon Relat. Elem.2022, 197, 13.
[27] Wu F.; Liang G. C.; Zhou G.; Liu Q. J.; Zhang C. C.; Yu J. J.; Dong X. H.; Song, Y. L. Lett. Org. Chem.2016, 13, 206.
[28] Li P.; Wang B.; Zhang X.; Batt S. M.; Besra G. S.; Zhang T.; Ma C.; Zhang D.; Lin Z.; Li G.; Huang H.; Lu, Y. Eur. J. Med. Chem.2018, 160, 157.
[29] Zhao H.; Zhao Y. Molecules,2023, 28, 25.
[30] Silva N. H. D.; Pyreddy S.; Blanch E. W.; Hügel H. M.; Maniam S. Bioorg. Chem.2021, 114, 105128.
[31] Qian Y. L.; Li B.; Xia P. J.; Wang J.; Xiang H. Y.; Yang H. Tetrahedron,2018, 74, 6821.
[32] Wang Y.; Chen Y. Tetrahedron Lett.,2017, 58, 1545.
[33] Shen P.; Guo Y.; Wei J.; Zhao H.; Zhai H.; Zhao Y. Synthesis,2020, 53, 1262.
[34] Chen S.; Yue J.; Liu X. L.; Wang J. X.; Zuo X.; Cao Y. Synth. Commun.2019, 49, 2425.
[35] Zhang, J.-D.; Li, Y.-L.; Yao, D.-M.; Liu, Y.; Cai, K.; Xiao, Y.-C.; Chen, F.-E. Org. Lett. 2026, 28, 5044.
