镍催化炔基与三氟乙酰亚胺氯和水的环化反应: 高效合成2-(三氟甲基)吲哚衍生物

doi:10.6023/cjoc202508002

摘要/Abstract

报道了一种镍催化的炔基与三氟乙酰亚胺氯和水的环化反应. 该反应可高效地构建结构多样的2-(三氟甲基)吲哚衍生物. 此策略具有广泛的底物普适性和优异的官能团兼容性. 值得注意的是, 产物(2,5-双(三氟甲基)-1H-吲哚-3-基)(苯基)甲酮(25)和(5-甲基-2-三氟甲基-1H-吲哚-3-基)(苯基)甲酮(26)对HepG2(人肝癌细胞)具有显著的抗增殖活性.

关键词: 镍催化, 环化, 三氟乙酰亚胺氯, 2-(三氟甲基)吲哚

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

引用此文

孙雨, 朱延涛, 张东, 倪春节. 镍催化炔基与三氟乙酰亚胺氯和水的环化反应: 高效合成2-(三氟甲基)吲哚衍生物[J]. 有机化学, 2026, 46(3): 1017-1026.

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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图/表 5

图式1. 过渡金属促进的三氟乙酰亚胺氯用于合成2-(三氟甲基)吲哚衍生物的环化反应

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

表1. 反应条件优化a

Table 1. Optimization of reaction conditions

图式2. 底物范围考察

Scheme 2. Investigation of substrate scope

图式3. 天然产物与药物分子的修饰

Scheme 3. Modifications of natural products and pharmaceutical molecules

图1. 抗肿瘤活性

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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