半胱氨酸的硫杂芳基化反应

doi:10.6023/cjoc202506011

摘要/Abstract

开发了一种利用廉价、易得的氯代杂芳烃, 对半胱氨酸衍生物进行S-杂芳基化的新方法. 该方法基于亲核芳香取代(S_NAr)反应机制, 具有操作简便、反应条件温和的优势, 同时展现出优异的官能团兼容性与化学选择性. 底物普适性考察结果表明, 涵盖多种N-保护基的半胱氨酸衍生物、含半胱氨酸的寡肽及各类氯代杂芳烃在内的底物, 均可通过该方法顺利转化, 获得良好产率. 放大实验进一步验证了该方法的实用性和绿色经济性. 该策略为温和条件下高效、选择性地修饰半胱氨酸及其他硫醇分子提供了新途径, 在蛋白质修饰和生物分子标记等领域展现出广阔的应用前景.

关键词: 半胱氨酸, 杂芳基化, 肽

A new method for S-heteroarylation of cysteine derivatives using affordable, readily available chlorinated hetero- aromatic compounds has been proposed. The reaction proceeds via nucleophilic aromatic substitution (S_NAr) under mild conditions and simple operation, exhibiting excellent tolerance to various functional groups and high chemical selectivity. The results of substrate scope investigation demonstrated that A wide range of substrates, including different N-protected cysteine derivatives, cysteine-containing peptides, and various chlorinated heteroaryl compounds, could be efficiently transformed via this protocol to afford the desired products in good yields. Scale-up experiments confirmed the practicality and eco-friendliness of this protocol. Overall, this strategy offers an efficient and selective approach to modify cysteine and other thiols under mild conditions with broad potential applications in protein modification and biomolecular labeling.

Key words: cysteine, heteroarylation, peptide

引用此文

张鑫, 李飞, 周晨星, 霍聪德. 半胱氨酸的硫杂芳基化反应[J]. 有机化学, 2026, 46(1): 189-198.

Xin Zhang, Fei Li, Chenxing Zhou, Congde Huo. S-Heteroarylation of Cysteines[J]. Chinese Journal of Organic Chemistry, 2026, 46(1): 189-198.

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图/表 5

Entry	Change from the standard conditions	Yield^b/%
1	None	93
2	w/o base	0
3	DMSO instead of MeCN	70
4	DMA instead of MeCN	75
5	ⁱPrOH instead of MeCN	85
6	MeCN/H₂O (V∶V=1∶1)	49
7	MeCN/H₂O (V∶V=2∶1)	60
8	MeCN/PBS (V∶V=1∶1)	40
9	Na₂CO₃ instead of K₂CO₃	17
10	K₃PO₄ instead of K₂CO₃	89
11	DIPEA instead of K₂CO₃	90

表1. 反应条件优化a

Table 1. Optimization of reaction conditions

图式1. 反应的化学选择性

Scheme 1. Chemo-selectivity of the reaction

表2. 半胱氨酸的底物范围a,b

Table 2. Scope of cysteine

表3. 杂芳基氯的底物范围a,b

Table 3. Scope of chlorinated heteroaromatic hydrocarbons

图式2. 放大实验和合成应用

Scheme 2. Scale-up experiment and synthetic applications

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