Nickel-Catalyzed Annulation of Alkynyl with Trifluoroacetimidoyl Chlorides and H2O: Facile Access to 2‑(Trifluoromethyl)indole Derivatives

doi:10.6023/cjoc202508002

Abstract

A nickel-catalyzed 5-exo-dig annulation of alkynyl with trifluoroacetimidoyl chlorides and H₂O was reported, which facilitates the streamlined assembly of structurally diverse 2-(trifluoromethyl)indole derivatives. This catalytic strategy demonstrates broad substrate compatibility and exceptional functional group tolerance. Furthermore, the antiproliferative potential of the obtained compounds was systematically evaluated against HepG2 (human hepatoma cells). Notably, (2,5-bis(tri- fluoromethyl)-1H-indol-3-yl)(phenyl)methanone (25) and (5-methyl-2-(trifluoromethyl)-1H-indol-3-yl)(phenyl)methanone (26) displayed a marked enhancement in antiproliferative potency.

Key words: nickel-catalysis, annulation, trifluoroacetimidoyl chloride, 2-(trifluoromethyl)indole

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Yu Sun, Yantao Zhu, Dong Zhang, Chunjie Ni. Nickel-Catalyzed Annulation of Alkynyl with Trifluoroacetimidoyl Chlorides and H₂O: Facile Access to 2‑(Trifluoromethyl)indole Derivatives[J]. Chinese Journal of Organic Chemistry, 2026, 46(3): 1017-1026.

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Fig. & Tab. 5

Scheme 1. Transition metal-promoted cyclizations for 2‑(tri- fluoromethyl)indole derivatives using trifluoroacetimidoyl chlorides

Entry	[Ni]	Ligand	Yield^b/%
1	NiBr₂	L1	62
2	NiBr₂(dme)	L1	61
3	NiCl₂	L1	56
4	Ni(ClO₄)₂•6H₂O	L1	58
5	Ni(OTf)₂	L1	69
6	Ni(acac)₂	L1	71
7	Ni(acac)₂	L2	68
8	Ni(acac)₂	L3	70
9	Ni(acac)₂	L4	65
10	Ni(acac)₂	Xantphos	ND^c
11	Ni(acac)₂	dppBz	81
12	Ni(acac)₂	DPPE	89
13	Ni(acac)₂	DPPP	72
14	Ni(acac)₂	DPPF	ND
15	Ni(acac)₂	DPEphos	ND
16^d	Ni(acac)₂	DPPE	72
17^e	Ni(acac)₂	DPPE	48
18^f	Ni(acac)₂	DPPE	Trace

Table 1. Optimization of reaction conditions

Scheme 2. Investigation of substrate scope

Scheme 3. Modifications of natural products and pharmaceutical molecules

Figure 1. Antitumour activity (a) Cytotoxicity of selective compounds against cancer cell lines HepG2 for 48 h using CCK-8 assay; (b) Flow cytometry analysis of apoptotic HepG2 cells that were treated with compounds 25 and 26 at increasing concentrations (5 and 10 µmol/L) for 48 h and stained with Annexin V/PI; (c) Flow cytometry analysis of reactive oxygen species (ROS) production in HepG2 cells treated with compounds 25 and 26 (5 and 10 µmol/L) for 24 h and stained with DCFH-DA.

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Nickel-Catalyzed Annulation of Alkynyl with Trifluoroacetimidoyl Chlorides and H₂O: Facile Access to 2‑(Trifluoromethyl)indole Derivatives

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