四丁基氟化铵促进的α-(三氟甲基)苯乙烯与硫酚的氢硫醇化反应

doi:10.6023/cjoc202512026

有机化学 ›› 2026, Vol. 46 ›› Issue (6): 2346-2357.DOI: 10.6023/cjoc202512026 上一篇下一篇

研究论文

四丁基氟化铵促进的α-(三氟甲基)苯乙烯与硫酚的氢硫醇化反应

张美^†, 陈嫚^†, 陈雨, 姚秋丽, 王安俊^*()

遵义医科大学药学院贵州省化学药物创制全省重点实验室贵州遵义 563000

收稿日期:2025-12-19 修回日期:2026-02-14 发布日期:2026-04-20
通讯作者: 王安俊
作者简介:
^† 共同第一作者
基金资助:
遵义市科技计划(遵市科合HZ字[2023]169号); 贵州省科技计划项目(黔科平台人才[2021]1350-005号); 贵州省科学技术厅(黔科合平台人才-CXTD[2022]012)

Tetrabutylammonium Fluoride-Promoted Hydrothiolation of α-(Trifluoromethyl)styrenes with Thiophenols

Mei Zhang, Man Chen, Yu Chen, Qiuli Yao, Anjun Wang^*()

Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals, School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000

Received:2025-12-19 Revised:2026-02-14 Published:2026-04-20
Contact: Anjun Wang
About author:
^† These authors contributed equally to this work.
Supported by:
Zunyi City Science and Technology Plan Project (Zun City Kehe HZ character [2023]169); Guizhou Province Science and Technology Plan Project (Guizhou Science Platform talent [2021]1350-005); Science and Technology Department of Guizhou Province (QKHPTRC-CXTD[2022]-012)

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摘要/Abstract

三氟甲基和硫醚基团被广泛地应用于药物分子的设计中. 报道了一种在无需额外添加溶剂条件下, 四丁基氟化铵(TBAF, 1 mol/L四氢呋喃溶液)促进的α-(三氟甲基)苯乙烯与硫酚的氢硫醇化反应. 该策略操作简单、条件温和, 并显示出优异的官能团耐受性和化学选择性. 该方法原子经济性高, 目标产物的收率最高可达95%, 为合成β-三氟甲基硫醚类化合物提供了另一种简洁、高效的途径.

关键词: 四丁基氟化铵(TBAF), 氢硫醇化反应, α-(三氟甲基)苯乙烯, β-三氟甲基硫醚

The trifluoromethyl and thioether groups are widely employed in the design of drug molecules. A hydrothiolation reaction of α-(trifluoromethyl)styrenes with thiophenols under solvent-free conditions is reported, which is promoted by tetrabutylammonium fluoride [TBAF, 1 mol/L in tetrahydrofuran (THF)]. This strategy features simple operation, mild reaction conditions, excellent functional group tolerance, and high chemoselectivity. The method demonstrates high atom economy, affording the target products in up to 95% yield, thus providing a concise and efficient alternative approach for the synthesis of β-trifluoromethyl thioethers.

Key words: tetrabutylammonium fluoride (TBAF), hydrothiolation reaction, α-(trifluoromethyl) styrene, β-trifluoromethyl thioethers

引用此文

张美, 陈嫚, 陈雨, 姚秋丽, 王安俊. 四丁基氟化铵促进的α-(三氟甲基)苯乙烯与硫酚的氢硫醇化反应[J]. 有机化学, 2026, 46(6): 2346-2357.

Mei Zhang, Man Chen, Yu Chen, Qiuli Yao, Anjun Wang. Tetrabutylammonium Fluoride-Promoted Hydrothiolation of α-(Trifluoromethyl)styrenes with Thiophenols[J]. Chinese Journal of Organic Chemistry, 2026, 46(6): 2346-2357.

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图/表 8

图1. 含硫醚结构的药物分子

Figure 1. Drug molecules containing thioether structures

图式1. 分子设计以及β-三氟甲基硫醚的合成方法

Scheme 1. Molecular design and synthesis methods of β-tri- fluoromethyl sulfide

Entry	Base (x equiv.)	Time/h	Atmosphere	Yield/%
1	K₂CO₃ (0.5)	12	Ar	—
2	Et₃N (0.5)	12	Ar	—
3	KF (0.5)	12	Ar	—
4	CsF ( 0.5)	12	Ar	—
5	TMAF (0.5)	12	Ar	Trace
6^c	TBAF•3H₂O (0.5)	12	Ar	90
7	TBAF•3H₂O (0.5)	12	Ar	91
8	TBAF (0.5)	12	Ar	95 (91)
9	DBN (0.5)	12	Ar	89
10	DBU (0.5)	12	Ar	92
11	TBAF (1.0 )	12	Ar	86
12	TBAF (0.4)	12	Ar	90
13	TBAF (0.3)	12	Ar	91
14	TBAF (0.2)	12	Ar	89
15	TBAF (0.1)	12	Ar	45
16	—	12	Ar	—
17	TBAF (0.5)	10	Ar	79
18	TBAF (0.5)	12	Air	61

表1. 反应条件优化的代表性结果a,b

Table 1. Representative results for the optimization of reaction conditions

表2. 底物普适性考察a,b

Table 2. Investigation of substrate scope

表3. 底物对各取代硫酚普适性考察a,b

Table 3. Investigation of the universality of substrates to each thiophenol

图式2. 克级规模合成和衍生化实验

Scheme 2. Gram-scale synthesis and derivatization experiment

图式3. 自由基抑制实验和氘标记研究

Scheme 3. Radical inhibition experiment and deuterium-labeling study

图式4. 可能的反应机理

Scheme 4. Plausible reaction mechanism

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四丁基氟化铵促进的α-(三氟甲基)苯乙烯与硫酚的氢硫醇化反应

Tetrabutylammonium Fluoride-Promoted Hydrothiolation of α-(Trifluoromethyl)styrenes with Thiophenols

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