三组分交叉偶联反应高效合成双芳基硫醚

doi:10.6023/cjoc202407024

摘要/Abstract

双芳基硫醚常存在于药物和天然产物中, 通常涉及金属交叉偶联反应、高温以及使用稳定性差、气味难闻的硫酚进行合成. 基于此, 研究了在无过渡金属催化条件下, 多氟芳烃、二芳基碘盐及硫代乙酸钾的三组分交叉偶联反应. 该反应通过商业化的硫代乙酸钾与两种缺电子芳烃经连续两次亲电取代反应, 合成了系列非对称的双芳基硫醚, 表现出了宽泛的底物适用范围和官能团兼容性. 此外, 通过一锅法氧化反应可以实现砜和亚砜类化合物的合成, 拓展了该策略的应用范围; 克级规模实验和衍生化实验均表现出优异的结果, 进一步证明了该反应具有潜在的应用价值. 通过对照、自由基抑制及中间体捕获实验阐明了其机制.

关键词: 无过渡金属, 多氟芳烃, 二芳基碘盐, 双芳基硫醚

Diaryl sulfides are found in drugs and natural products, yet their synthesis traditionally requires metal-catalyzed cross-coupling reactions, high temperatures, and the use of the air-sensitive and extremely odorous thiophenols. A novel transition-metal-free strategy for the synthesis of unsymmetric diaryl sulfides via a three-component cross-coupling of polyfluoro- arenes, diaryliodide salts and potassium thioacetate is reported. This approach enables the formation of a diverse array of unsymmetric diaryl thioethers through two successive electrophilic substitution reactions involving commercially available potassium thioacetate and two electron-deficient aromatic hydrocarbons, demonstrating broad substrate scope and functional group compatibility. Additionally, this strategy facilitates the synthesis of sulfones and sulfoxides via a one-pot oxidation reaction, thereby extending its applicability. Gram-scale reactions and derivatization experiments have shown excellent results, further proving the potential application value of this reaction. Mechanistic insights were elucidated through control, radical inhibition and intermediate capture experiments.

Key words: transition metal-free, polyfluoroarenes, diaryliodonium salts, diaryl sulfides

引用此文

刘梦琴, 陈贻庭, 张榉元, 周和烨, 秦涛, 刘彬. 三组分交叉偶联反应高效合成双芳基硫醚[J]. 有机化学, 2025, 45(4): 1283-1296.

Mengqin Liu, Yiting Chen, Juyuan Zhang, Heye Zhou, Tao Qin, Bin Liu. Efficient Synthesis of Diaryl Sulfides via Three Component Cross Coupling[J]. Chinese Journal of Organic Chemistry, 2025, 45(4): 1283-1296.

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图/表 8

图1. 一些具有生物活性的二芳基硫化物

Figure 1. Some biologically active diaryl sulfide compounds

图式1. 二芳基硫醚的合成方法

Scheme 1. Synthetic methods for giving diaryl sulfides

Entry	Molar ratio of 1a/2/3a	2	Temp./℃	Solvent	Yield^b/% of 4a
1^c	1/1.5/2	2a	80	DMSO	Trace
2^c	1/1.5/2	2b	80	DMSO	42
3	1/1.5/2	2c	80	DMSO	69
4^d	1/1.5/2	2d	80	DMSO	56
5	1/1.5/2	2e	80	DMSO	55
6	1/1.5/2	2f	80	DMSO	43
7	1/1.5/2	2c	80	DMF	57
8	1/1.5/2	2c	80	Acetone	43
9	1/1.5/2	2c	80	THF	Trace
10	1/1.5/2	2c	80	CH₃CN	Trace
11	1/1.5/2	2c	80	Toluene	n.d.
12	1/1.5/2	2c	80	DCE	n.d.
13	1/1.5/2	2c	60	DMSO	58
14	1/1.5/2	2c	100	DMSO	73
15	1/2/2	2c	100	DMSO	82
16	1/2/1.5	2c	100	DMSO	61

表1. 反应条件优化a

Table 1. Screening reaction conditions

表2. 合成产物4的底物范围a

Table 2. Substrate scope for the synthesis of product 4

表3. 合成产物5的底物范围a

Table 3. Substrate scope for the synthesis of product 5

表4. 合成产物6a和7b的底物范围

Table 4. Substrate scope for the synthesis of product 6a and 7b

图式2. 克级合成、产物的衍生化和复杂结构的天然产物和药物衍生物的修饰

Scheme 2. Gram-scale synthesis, derivatization of the products and structurally more complicated modification

图式3. 机理研究及推测

Scheme 3. Mechanistic studies and speculations

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