路易斯酸促进的不饱和酰胺的分子内亲核加成杂环化反应合成2-噁唑啉衍生物及其在细胞成像中的应用

doi:10.6023/cjoc202201036

有机化学 ›› 2022, Vol. 42 ›› Issue (7): 2155-2163.DOI: 10.6023/cjoc202201036 上一篇下一篇

研究论文

路易斯酸促进的不饱和酰胺的分子内亲核加成杂环化反应合成2-噁唑啉衍生物及其在细胞成像中的应用

陈学荣^a, 祁亮^a, 黄晋培^a, 朱伟伟^b^,^*(), 周益峰^a^,^*()

^a中国计量大学生命科学学院杭州 310018
^b中山大学药学院广州 510006

收稿日期:2022-01-22 修回日期:2022-02-17 发布日期:2022-08-09
通讯作者: 朱伟伟, 周益峰
作者简介:
^† 共同第一作者
基金资助:
国家自然科学基金(22108264)

Lewis Acid Promoted Intramolecular Nucleophilic Heterocyclization of Unsaturated Amides for the Synthesis of 2-Oxazolines and Their Applications in Imaging of Living Cells

Xuerong Chen^a, Liang Qi^a, Jinpei Huang^a, Weiwei Zhu^b(), Yifeng Zhou^a()

^aCollege of Life Sciences, China Jiliang University, Hangzhou 310018
^bSchool of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006

Received:2022-01-22 Revised:2022-02-17 Published:2022-08-09
Contact: Weiwei Zhu, Yifeng Zhou
About author:
^† These authors contributed equally to this work
Supported by:
National Natural Science Foundation of China(22108264)

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1. 路易斯酸促进的不饱和酰胺的分子内亲核加成杂环化反应合成2-噁唑啉衍生物及其在细胞成像中的应用.pdf(6196KB)

摘要/Abstract

2-噁唑啉及其衍生物是有机合成、材料化学和生物医药中重要的有机结构单元. 报道了一种高效、反应条件温和且无金属参与的路易斯酸促进的分子内亲核杂环化反应合成2-噁唑啉衍生物的方法(80%~94%分离产率), 并将合成得到的噁唑啉衍生物用于细胞成像研究, 结果表明, 合成的噁唑啉衍生物在细胞成像实验中表现出了良好的细胞相容性和成像性.

关键词: 路易斯酸, 杂环化, 2-噁唑啉, 细胞成像

2-Oxazolines and their derivatives are important scaffolds present in the fields of organic synthesis, material science and biomedicine. An efficient, mild and metal-free process to synthesize 2-oxazoline derivatives was reported. Various 2-oxazoline derivatives were synthesized through the Lewis acid-mediated intramolecularly nucleophilic heterocyclization of unsaturated amides in high to excellent yields (80%~94% isolated yields). Besides, the experiments of imaging of living cells were conducted to verify the proper fluorescence properties of the 2-oxazoline derivative. The results indicated that the probe had good cellular compatibility, as well as the potential to track spatial dynamics in living cells.

Key words: Lewis acid, gheterocyclization, 2-oxazoline, cell imaging

引用此文

陈学荣, 祁亮, 黄晋培, 朱伟伟, 周益峰. 路易斯酸促进的不饱和酰胺的分子内亲核加成杂环化反应合成2-噁唑啉衍生物及其在细胞成像中的应用[J]. 有机化学, 2022, 42(7): 2155-2163.

Xuerong Chen, Liang Qi, Jinpei Huang, Weiwei Zhu, Yifeng Zhou. Lewis Acid Promoted Intramolecular Nucleophilic Heterocyclization of Unsaturated Amides for the Synthesis of 2-Oxazolines and Their Applications in Imaging of Living Cells[J]. Chinese Journal of Organic Chemistry, 2022, 42(7): 2155-2163.

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图/表 7

Scheme 1. Application examples and synthesis of 2-oxazolines

Entry	LA^b	Solvent	Temperature/℃	Yield^c/%
1	BF₃•Et₂O	DCM	0	12
2	BF₃•Et₂O	DCM	25	65
3	TFA	DCM	25	0
4	AcOH	DCM	25	0
5	MsOH	DCM	25	0
6	FeCl₃	DCM	25	0
7	ZnCl₂	DCM	25	0
8	MeOTf	DCM	25	0
9	TMSOTf	DCM	25	85
10	TMSOTf	MeCN	25	82
11	TMSOTf	C₆H₅Cl	25	79
12	TMSOTf	CHCl₃	25	77
13	TMSOTf	DCE	25	94
14	TMSOTf	DMF	25	Trace
15^d	TMSOTf	DCE	25	Trace

Table 1. Optimization of the reaction conditionsa

Table 2. Substrat scope of the TMSOTf promoted heterocyclizationa

Scheme 2. Possible reaction mechanism

Figure 3. Confocal microscope images of Hela cells incubated with 11b (20 μmol/L) for different incubation times (λex=405 nm, λem=470±20 nm. Scale bar=20 μm)

Figure 4. Co-localization of 11b (20 μmol/L, 1 h) with BODIPY 493/503 (100 nmol/L, 30 min), LTR (100 nmol/L, 30 min) and MTR (100 nmol/L, 30 min) in HeLa cells by confocal microscopy images Scale bar: 20 μm. λex/em=405/(470±20) nm for 11b, λex/em=488/(510±10) nm for BODIPY 493/503, λex/em=561/(580±10) nm for MTR and LTR.

Figure 4. Z-Stack scans images of Hela cells incubated with 11b (20 μmol/L) for 1 h (λex=405 nm, λem=470±20 nm. Scale bar=20 μm)

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路易斯酸促进的不饱和酰胺的分子内亲核加成杂环化反应合成2-噁唑啉衍生物及其在细胞成像中的应用

Lewis Acid Promoted Intramolecular Nucleophilic Heterocyclization of Unsaturated Amides for the Synthesis of 2-Oxazolines and Their Applications in Imaging of Living Cells

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