Synthesis of C2-Spiroindolines Based on the Cascade Reaction of 2-Aryl-3H-indoles with Cyclopropanols

doi:10.6023/cjoc202406001

Abstract

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

Cite this article

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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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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