4-二甲氨基吡啶(DMAP)促进的异喹啉两性离子与α-溴代苯乙酮的[5＋1]环化反应: 氢化1,4-噻嗪并异喹啉三环衍生物的高效合成

doi:10.6023/cjoc202502008

有机化学 ›› 2025, Vol. 45 ›› Issue (9): 3429-3440.DOI: 10.6023/cjoc202502008 上一篇下一篇

研究论文

4-二甲氨基吡啶(DMAP)促进的异喹啉两性离子与α-溴代苯乙酮的[5＋1]环化反应: 氢化1,4-噻嗪并异喹啉三环衍生物的高效合成

蔡压男, 孟祥太^*()

天津理工大学化学化工学院天津市有机太阳能电池与光化学转换重点实验室天津 300384

收稿日期:2025-04-24 修回日期:2025-05-07 发布日期:2025-05-15
基金资助:
国家自然科学基金(21403154)

4-Dimethylamino-pyridine (DMAP)-Promoted [5＋1] Annulation of Isoquinolinium Zwitterions with α-Bromophenones: An Efficient Approach to Hydrogenated 1,4-Thiazino[2,3-a]isoquinoline Tricyclic Derivatives

Yanan Cai, Xiangtai Meng^*()

Tianjin Key Laboratory of Organic Solar Cells and Photochemical Conversion, School of Chemistry & Chemical Engineering, Tianjin University of Technology, Tianjin 300384

Received:2025-04-24 Revised:2025-05-07 Published:2025-05-15
Contact: *E-mail: xtmeng@tjut.edu.cn
Supported by:
National Natural Science Foundation of China(21403154)

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摘要/Abstract

开发了一种高效的合成策略, 通过4-二甲氨基吡啶(DMAP)促进异喹啉1,4-两性离子与α-溴代苯乙酮的[5＋1]环化反应, 成功构建了氢化1,4-噻嗪并[3,4-a]异喹啉三环体系. 该反应体系具有良好的底物普适性和电子兼容性, 能够以中等至良好的收率高效地合成了一系列具有不同取代基和电子特性的氢化1,4-噻嗪并[3,4-a]异喹啉衍生物. 值得注意的是, 尽管该反应表现出中等的立体选择性, 但通过柱层析技术可有效分离两种非对映异构体, 为后续药物先导化合物的筛选和结构优化提供了重要的分子多样性基础, 也为构建结构复杂的含氮、硫杂环化合物提供了一种简便、高效的方法, 在药物化学和有机合成领域具有潜在的应用价值.

关键词: [5＋1]环化反应, 异喹啉衍生物, 1,4-噻嗪衍生物

An efficient strategy for construction of tricyclic thiazino[3,4-a]isoquinolines has been achieved via 4-dimethyl- amino-pyridine (DMAP) promoted [5＋1] annulation of simple and readily available isoquinoline 1,4-zwitterion with α-bro- moketone. This protocol showed good substrate compatibility as an array of structurally and electronically diverse thiazino[3,4-a]isoquinolines prepared efficiently in moderate to good yields. It is particularly emphasized that although this reaction exhibits moderate stereoselectivity, the two diastereomers can be separated by column chromatography, providing an important molecular diversity foundation for the screening and structural optimization of subsequent drug lead compounds, as well as a simple and efficient method for constructing complex nitrogen-containing and sulfur-containing heterocyclic compounds. It has potential application value in the fields of medicinal chemistry and organic synthesis.

Key words: [5＋1] annulation, isoquinoline derivative, 1,4-thiazine derivative

引用此文

蔡压男, 孟祥太. 4-二甲氨基吡啶(DMAP)促进的异喹啉两性离子与α-溴代苯乙酮的[5＋1]环化反应: 氢化1,4-噻嗪并异喹啉三环衍生物的高效合成[J]. 有机化学, 2025, 45(9): 3429-3440.

Yanan Cai, Xiangtai Meng. 4-Dimethylamino-pyridine (DMAP)-Promoted [5＋1] Annulation of Isoquinolinium Zwitterions with α-Bromophenones: An Efficient Approach to Hydrogenated 1,4-Thiazino[2,3-a]isoquinoline Tricyclic Derivatives[J]. Chinese Journal of Organic Chemistry, 2025, 45(9): 3429-3440.

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图/表 8

Figure 1. Combination of privileged scaffolds

Scheme 1. Selected annulations of isoqunoline 1,4-zwitterionic thiolates

Entry	Base	Solvent	Yield^b/%
Entry	Base	Solvent	3a	4a
1	K₂CO₃	DCM	29	44
2	NaOH	DCM	21	66
3	NaH	DCM	25	58
4	DMAP	DCM	20	66
5	DABCO	DCM	11	49
6	DIPEA	DCM	41	55
7	CH₃ONa	DCM	23	66
8	DMAP	CH₃CN	11	81
9	DMAP	Toluene	9	28
10	DMAP	CH₃OH	11	49
11	DMAP	CH₃Cl	9	25
12	DMAP	C₆H₅Cl	4	53
13	DMAP	THF	17	49
14	DMAP	Dioxane	10	53
15^c	DMAP	CH₃CN	14	60
16^d	DMAP	CH₃CN	10	57
17^e	DMAP	CH₃CN	14	47
18^f	DMAP	CH₃CN	11	54
19^g	DMAP	CH₃CN	8	40

Table 1. Optimization of reaction conditionsa

Table 2. Substrate scope of α-bromoketonea

Figure 2. X-ray crystal structures of 3a and 4a

Table 3. Substrate scope of isoquinoline 1,4-zwitteriona

Scheme 2. Transformations and large-scale experiments

Scheme 3. Proposed mechanism

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4-二甲氨基吡啶(DMAP)促进的异喹啉两性离子与α-溴代苯乙酮的[5＋1]环化反应: 氢化1,4-噻嗪并异喹啉三环衍生物的高效合成

4-Dimethylamino-pyridine (DMAP)-Promoted [5＋1] Annulation of Isoquinolinium Zwitterions with α-Bromophenones: An Efficient Approach to Hydrogenated 1,4-Thiazino[2,3-a]isoquinoline Tricyclic Derivatives

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