基于2-芳基-3H-吲哚与环丙醇的串联反应合成C2-螺环吲哚啉衍生物

doi:10.6023/cjoc202406001

摘要/Abstract

报道了一种基于2-芳基-3H-吲哚与环丙醇的串联反应合成C2-螺环吲哚啉衍生物的新方法. 产物的生成经历了三价铑催化下2-芳基-3H-吲哚的芳基C(sp²)—H键烷基化和随后的分子内螺环化. 在该串联反应过程中, 环丙醇不仅是烷基化试剂, 而且作为掩蔽的亲核试剂参与了螺环骨架的构建; 而空气作为一种经济且可持续的氧化剂, 有效地促进了催化剂的再生. 另外, 该方法也可用于一些含有药物分子骨架的杂化体化合物的合成. 所开发的方法具有底物易得、过程简洁、原子经济性高、官能团耐受性好、易于放大等优点.

关键词: C2-螺环吲哚啉, 合成, 碳氢键活化, 串联反应, 2-芳基-3H-吲哚, 环丙醇

A novel synthesis of C2-spiroindoline derivatives based on the cascade reaction of 2-aryl-3H-indoles with cyclo- propanols is presented. The formation of product involves Rh(III)-catalyzed aryl C(sp²)—H bond alkylation of 2-aryl- 3H-indole, which is followed by intramolecular spiroannulation. In this tandem process, cyclopropanol acts as not only an alkylating agent but also a masked nucleophile to take part in the construction of the spirocyclic scaffold. Meanwhile, air acts as an economical and sustainable oxidant to promote the regeneration of the active catalyst. By using this method, hybrid compounds containing the central scaffolds of some clinical drugs were prepared effectively. In general, this newly developed method has advantages such as easily obtainable substrates, concise synthetic procedure, excellent atom-economy, good compatibility with diverse functional groups and ready scalability.

Key words: C2-spiroindolines, synthesis, C—H bond activation, cascade reaction, 2-aryl-3H-indoles, cyclopropanols

引用此文

杨雪莹, 徐园双, 张新迎, 范学森. 基于2-芳基-3H-吲哚与环丙醇的串联反应合成C2-螺环吲哚啉衍生物[J]. 有机化学, 2025, 45(2): 694-706.

Xueying Yang, Yuanshuang Xu, Xinying Zhang, Xuesen Fan. Synthesis of C2-Spiroindolines Based on the Cascade Reaction of 2-Aryl-3H-indoles with Cyclopropanols[J]. Chinese Journal of Organic Chemistry, 2025, 45(2): 694-706.

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参考文献 14

[1]	(a) Katayama, K.; Arai, Y.; Murata, K.; Saito, S.; Nagata, T.; Takashima, K.; Yoshida, A.; Masumura, M.; Koda, S.; Okada, H.; Muto, T. Bioorg. Med. Chem. 2020, 28, 115348. pmid: 33381970
	(b) Hiesinger, K.; Dar’in, D.; Proschak, E.; Krasavin, M. J. Med. Chem. 2021, 64, 150. doi: 10.1021/acs.jmedchem.0c01473 pmid: 33381970
	(c) Wang, Q.; Song, H.; Wang, Q. Chin. Chem. Lett. 2022, 33, 859. pmid: 33381970
	(d) Divar, M.; Edraki, N.; Damghani, T.; Moosavi, F.; Mohabbati, M.; Alipour, A.; Pirhadi, S.; Saso, L.; Khabnadideh, S.; Firuzi, O. Bioorg. Med. Chem. 2023, 90, 117367. pmid: 33381970
[2]	(a) Bariwal, J.; Voskressensky, L.; Vandereycken, E. Chem. Soc. Rev. 2018, 47, 3831.
	(b) Ji, Y.; He, X.; Peng, C.; Huang, W. Org. Biomol. Chem. 2019, 17, 2850.
	(c) Dhote, P. S.; Patel, P.; Vanka, K.; Ramana, C. V. Org. Biomol. Chem. 2021, 19, 7970.
[3]	(a) Zhang, B.; Zhang, X.; Hu, B.; Sun, D.; Wang, S.; Zhang- Negrerie, D.; Du, Y. Org. Lett. 2017, 19, 902. doi: 10.1021/acs.orglett.7b00058 pmid: 28134531
	(b) Marien, N.; Reddy, B. N.; De Vleeschouwer, F.; Goderis, S.; Van Hecke, K.; Verniest, G. Angew. Chem., Int. Ed. 2018, 57, 5660. pmid: 28134531
	(c) Xu, H.; Yamaguchi, S.; Mitsudome, T.; Mizugaki, T. Eur. J. Org. Chem. 2022, e202200826. pmid: 28134531
	(d) Sah, P.; Gond, A. K.; Saini, G.; Kapur, M. Org. Lett. 2023, 25, 9170. pmid: 28134531
[4]	(a) Fu, W.; Song, Q. Org. Lett. 2018, 20, 393.
	(b) Zhao, Y.-L.; An, J.-X.; Yang, F.-F.; Guan, X.; Fu, X.-Z.; Li, Z.-Q.; Wang, D.-P.; Zhou, M.; Yang, Y.-Y.; He, B. Adv. Synth. Catal. 2022, 364, 1277.
	(c) Li, C.; Zhao, B.; Mao, G.; Deng, G.-J. Chem. Commun. 2023, 59, 7044.
	(d) Dong, X.; Liu, X.; Wang, L.; Zhang, Y.; Li, J.; Tian, L.; Zhao, Y. Org. Lett. 2023, 25, 9170.
[5]	(a) Kong, L.; Wang, M.; Zhang, F.; Xu, M.; Li, Y. Org. Lett. 2016, 18, 6124.
	(b) Liu, X.; Yan, X.; Yu, J.-H.; Tang, Y.; Wang, K.; Zhang, H. Org. Lett. 2019, 21, 5626.
	(c) Liu, X.; Yan, X.; Tang, Y.; Jiang, C.-S.; Yu, J.-H.; Wang, K.; Zhang, H. Chem. Commun. 2019, 55, 6535.
	(d) Nagare, Y. K.; Shah, I. A.; Yadav, J.; Pawar, A. P.; Rangan, K.; Choudhary, R.; Iype, E.; Kumar, I. J. Org. Chem. 2022, 87, 15771.
[6]	(a) Wang, J.; Chen, Y.; Du, W.; Chen, N.; Fu, K.; He, Q.; Shao, L. Tetrahedron 2022, 127, 133101.
	(b) Reddy, C. R.; Theja, A.; Srinivasu, E.; Subbarao, M. Org. Lett. 2024, 26, 68.
[7]	(a) Sinha, S. K.; Ghosh, P.; Jain, S.; Maiti, S.; Al-Thabati, S. A.; Alshehri, A.; Mokhtar, M.; Maiti, D. Chem. Soc. Rev. 2023, 52, 7461. pmid: 34486584
	(b) Seth, K. Org. Chem. Front. 2022, 9, 3102. pmid: 34486584
	(c) Prabagar, B.; Yang, Y.; Shi, Z. Chem. Soc. Rev. 2021, 50, 11249. doi: 10.1039/d0cs00334d pmid: 34486584
	(d) Liu, B.; Romine, A. M.; Rubel, C. Z.; Engle, K. M.; Shi, B.-F. Chem. Rev. 2021, 121, 14957. pmid: 34486584
	(e) Zhou, Q.; Li, B.; Zhang, X.; Fan, X. Org. Biomol. Chem. 2024, 22, 2324. pmid: 34486584
	(f) Shang, M.; Zhang, L.; Chen, M.; Hu, W.; He, X.; Lu, H. Chin. J. Org. Chem. 2022, 42, 3816 (in Chinese). pmid: 34486584
	(商铭洲, 张兰兰, 陈淼淼, 胡汪成, 何心伟, 陆红健, 有机化学, 2022, 42, 3816.) doi: 10.6023/cjoc202205039 pmid: 34486584
	(g) Fu, L.; Xu, W.; Pu, M.; Wu, Y.-D.; Liu, Y.; Wan, J.-P. Org. Lett. 2022, 24, 3003. pmid: 34486584
	(h) Chen, D.; Zhou, L.; Liu, Y.; Wan, J.-P. Chem. Commun. 2023, 59, 4036. pmid: 34486584
	(i) Chen, D.; Wan, C.; Liu, Y.; Wan, J.-P. J. Org. Chem. 2023, 88, 4833. pmid: 34486584
[8]	(a) Huang, J.-R.; Qin, L.; Zhu, Y.-Q.; Song, Q.; Dong, L. Chem. Commun. 2015, 51, 2844. pmid: 37144839
	(b) Hu, W.-B.; Qiu, Y.-Q.; Wei, W.-Y.; Li, Q.; Xu, Y.-J. J. Org. Chem. 2022, 87, 6179. pmid: 37144839
	(c) Gao, J.; Luo, K.; Wei, X.; Wang, H.; Liu, H.; Zhou, Y. Org. Lett. 2023, 25, 3341. doi: 10.1021/acs.orglett.3c00445 pmid: 37144839
	(d) Yang, Z.; Li, P.; Chen, Z.; Wu, X.-F. Adv. Synth. Catal. 2023, 365, 3855. pmid: 37144839
[9]	(a) Nikolaev, A.; Orellana, A. Synthesis 2016, 48, 1741. pmid: 33085458
	(b) Mills, L. R.; Rousseaux, S. A. L. Eur. J. Org. Chem. 2019, 1, 8. pmid: 33085458
	(c) McDonald, T. R.; Mills, L. R.; West, M. S.; Rousseaux, S. A. L. Chem. Rev. 2021, 121, 3. doi: 10.1021/acs.chemrev.0c00346 pmid: 33085458
[10]	(a) Zhou, X.; Yu, S.; Kong, L.; Li, X. ACS Catal. 2016, 6, 647. pmid: 36088653
	(b) Chen, M.-W.; Lou, M.; Deng, Z.; Yang, Q.; Peng, Y. Asian J. Org. Chem. 2021, 10, 192. pmid: 36088653
	(c) Ramachandran, K.; Anbarasan, P. Chem. Commun. 2022, 58, 10536. pmid: 36088653
	(d) Paul, T.; Basak, S.; Punniyamurthy, T. Org. Lett. 2022, 24, 6000. pmid: 36088653
	(e) Ramachandran, K.; Anbarasan, P. Org. Lett. 2022, 24, 6745. doi: 10.1021/acs.orglett.2c02527 pmid: 36088653
	(f) Liu, Z.-K.; Zeng, J.-H.; Zhan, Z.-P. Org. Chem. Front. 2023, 10, 399. pmid: 36088653
[11]	(a) Chen, J.; Yin, C.; Zhou, J.; Yu, C.; Eur. J. Org. Chem. 2021, 6, 915.
	(b) Wang, S.; Miao, E.; Wang, H.; Song, B.; Huang, W.; Yang, W. Chem. Commun. 2021, 57, 5929.
	(c) Jiang, J.; Liu, J.; Yang, Z.; Zheng, L.; Liu, Z.-Q. Adv. Synth. Catal. 2022, 364, 2540.
	(d) Chen, W.; Mao, Y.; Wang, M.; Ling, F.; Li, C.; Chen, Z.; Yao, J. Org. Biomol. Chem. 2023, 21, 775.
[12]	(a) Guo, C.; Li, B.; Liu, H.; Zhang, X.; Fan, X. Org. Lett. 2019, 21, 7189.
	(b) Zhou, Q.; Song, X.; Zhang, X.; Fan, X. Org. Chem. Front. 2021, 8, 4131.
	(c) Song, X.; Wang, K.; Xue, L.; Yu, H.; Zhang, X.; Lee, R. Fan, X. Org. Chem. Front. 2022, 9, 4583.
[13]	(a) He, X.; Liu, K.; Yan, S.; Wang, Y.; Jiang, Y.; Zhang, X.; Fan, X. J. Org. Chem. 2024, 89, 1880.
	(b) Hu, B.; Chen, G.; Zhao, J.; Xue, L.; Jiang, Y.; Zhang, X.; Fan, X. J. Org. Chem. 2021, 86, 10330.
	(c) Cai, X.; Song, X.; Zhu, Q.; Zhang, X.; Fan, X. J. Org. Chem. 2022, 87, 11048.
	(d) Yang, C.; Zhang, X.; Fan, X. Org. Chem. Front. 2023, 10, 4282.
	(e) Zhou, Q.; Song, X.; Zhang, X.; Fan, X. Org. Lett. 2022, 24, 1280.
	(f) Yu, C.; Xu, Y.; Zhang, X.; Fan, X. Org. Lett. 2022, 24, 9473.
	(g) Wang, K.; Sun, Y.; Li, B.; Zhang, X.; Fan, X. Org. Lett. 2024, 26, 3091.
[14]	Li, Y.; Li, B.; Wang, W.; Huang, W.; Zhang, X.; Chen, K.; Shi, Z. Angew. Chem. 2011, 123, 2163.

Entry		Additive	Solvent	Yield^b/%
1	[RhCp*Cl₂]₂		EtOH	36
2	[Ru(p-cymene)Cl]₂		EtOH	Trace
3	[IrCp*Cl₂]₂		EtOH	ND
4	[RhCp*(MeCN)₃](SbF₆)₂		EtOH	47
5	[CoCp*(CO)I₂]		EtOH	ND
6	[RhCp*(MeCN)₃](SbF₆)₂		TFE	ND
7	[RhCp*(MeCN)₃](SbF₆)₂		DCE	35
8	[RhCp*(MeCN)₃](SbF₆)₂		Toluene	50
9	[RhCp*(MeCN)₃](SbF₆)₂		MeCN	30
10	[RhCp*(MeCN)₃](SbF₆)₂		THF	36
11	[RhCp*(MeCN)₃](SbF₆)₂		DMF	Trace
12	[RhCp*(MeCN)₃](SbF₆)₂	K₂CO₃	Toluene	Trace
13	[RhCp*(MeCN)₃](SbF₆)₂	PivOH	Toluene	55
14	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	61
15	[RhCp*(MeCN)₃](SbF₆)₂	HOAc	Toluene	57
16	[RhCp*(MeCN)₃](SbF₆)₂	1-AdCO₂H	Toluene	59
17^c	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	62
18^d	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	57
19^c,e	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	73
20^c,e		TMB	Toluene	ND
21^c,e,f	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	Trace
22^c,e,g	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	63

Entry		Additive	Solvent	Yield^b/%
1	[RhCp*Cl₂]₂		EtOH	36
2	[Ru(p-cymene)Cl]₂		EtOH	Trace
3	[IrCp*Cl₂]₂		EtOH	ND
4	[RhCp*(MeCN)₃](SbF₆)₂		EtOH	47
5	[CoCp*(CO)I₂]		EtOH	ND
6	[RhCp*(MeCN)₃](SbF₆)₂		TFE	ND
7	[RhCp*(MeCN)₃](SbF₆)₂		DCE	35
8	[RhCp*(MeCN)₃](SbF₆)₂		Toluene	50
9	[RhCp*(MeCN)₃](SbF₆)₂		MeCN	30
10	[RhCp*(MeCN)₃](SbF₆)₂		THF	36
11	[RhCp*(MeCN)₃](SbF₆)₂		DMF	Trace
12	[RhCp*(MeCN)₃](SbF₆)₂	K₂CO₃	Toluene	Trace
13	[RhCp*(MeCN)₃](SbF₆)₂	PivOH	Toluene	55
14	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	61
15	[RhCp*(MeCN)₃](SbF₆)₂	HOAc	Toluene	57
16	[RhCp*(MeCN)₃](SbF₆)₂	1-AdCO₂H	Toluene	59
17^c	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	62
18^d	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	57
19^c,e	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	73
20^c,e		TMB	Toluene	ND
21^c,e,f	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	Trace
22^c,e,g	[RhCp*(MeCN)₃](SbF₆)₂	TMB	Toluene	63

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