卤键促进的2-溴丙腈衍生物与香豆素/喹啉酮的交叉偶联反应: 合成与转化

doi:10.6023/cjoc202504009

摘要/Abstract

开发了一种由卤键促进的 2-溴丙腈衍生物与香豆素/喹啉酮类化合物的交叉偶联反应. 该方法反应体系简单, 反应条件温和, 并能以中等至良好的收率获得目标产物. 目标化合物中的氰基官能团可在温和条件下高效转化为 2H-四唑衍生物. 使用酯类类似物进行了对比研究, 结果显示其反应活性相较于氰基对应物显著降低, 这凸显了氰基在该转化过程中的重要作用. 初步细胞实验表明, 化合物4b选择性地杀伤MDA-MB-231细胞, 其IC₅₀值为(22.8±1.3) μmol/L, 其他多数化合物对肿瘤细胞和HL-7702正常细胞均表现出无毒或者较低毒性. 上述初步的活性筛选结果为后续抗氧化、抗菌等其他生物活性的深入研究奠定了基础.

关键词: 卤键, 香豆素/喹啉酮, 2-溴丙腈衍生物, 偶联反应

A halogen bond-promoted cross-coupling reaction between 2-bromopropionitrile derivatives and coumarin/quino- linone compounds was reported. The developed methodology features a simple reaction system, mild conditions, and provides target products in moderate to good yields. The cyano functional group in the obtained compounds could be efficiently converted into 2H-tetrazole derivatives under mild conditions. Comparative studies using ester analogs demonstrated significantly reduced reactivity compared to their cyano counterparts, highlighting the crucial role of the cyano group in this transformation. Preliminary cellular experiments revealed that compound 4b selectively inhibited MDA-MB-231 cells with an IC₅₀ value of (22.8±1.3) μmol/L, while most other compounds exhibited non-toxic or low toxicity toward both tumor cells and HL-7702 normal cells. These findings establish a foundation for further investigations into other biological activities such as antioxidant and antibacterial properties.

Key words: halogen bond, coumarins/quinolinones, 2-bromopropionitrile derivatives, cross-coupling reaction

引用此文

温吉林, 郭鹏, 蒲国良, 满雪玉, 贺春阳. 卤键促进的2-溴丙腈衍生物与香豆素/喹啉酮的交叉偶联反应: 合成与转化[J]. 有机化学, 2025, 45(12): 4405-4416.

Jilin Wen, Peng Guo, Guoliang Pu, Xueyu Man, Chun-Yang He. Halogen-Bond-Promoted Direct Cross-Coupling of 2-Bromo- propionitrile Derivatives with Coumarins/Quinolinones: Synthesis and Transformation[J]. Chinese Journal of Organic Chemistry, 2025, 45(12): 4405-4416.

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图/表 8

图1. (a)部分含氰基的药物; (b)以香豆素为核心结构的药物分子

Figure 1. (a) Drugs containing a cyano group; (b) coumarin-based drug molecules

图式1. 反应设计

Scheme 1. Reaction design

Entry	Electron donor	LED light/nm	Solvent	Yield^b/%
1	DMAP	410~415	DMSO	52
2	DMAP	410~415	DCM	N. D.
3	DMAP	410~415	THF	N. D.
4	DMAP	410~415	CH₃OH	N. D.
5	DMAP	410~415	DMF	31
6	DMAP	410~415	CH₃CN	N. D.
7	PPh₃	410~415	DMSO	N. D.
8	HE	410~415	DMSO	N. D.
9	PhOH	410~415	DMSO	N. D.
10	Et₃N	410~415	DMSO	44
11	DBU	410~415	DMSO	Trace
12	DIPEA	410~415	DMSO	16
13	DMAP	390~395	DMSO	38
14^c	DMAP	440~445	DMSO	49
15^d	DMAP	410~415	DMSO	41
16^e	DMAP	410~415	DMSO	58
17^f	DMAP	410~415	DMSO	68
18^g	DMAP	410~415	DMSO	69
19	—	410~415	DMSO	N.D.
20^h	DMAP	—	DMSO	N.D.

表1. 1a与香豆素(2a)交叉偶联反应优化结果a

Table 1. Representative results for the optimization of cross-coupling between 1a and coumarin (2a)a

图式2. 化合物1与香豆素(2a)交叉偶联反应的底物适用性考察a

Scheme 2. Investigation of substrate scope in the cross-coupling reaction of compound 1 with coumarin (2a) a Reaction conditions (unless otherwise specified): 1 (0.2 mmol, 1.0 equiv.), 2a (2.0 mmol, 10.0 equiv.), DMAP (2.0 equiv.), DMSO (1.0 mL), purple LED (410~415 nm 10 W), 30 ℃ 12 h. b Recovery ratio of coumarin. c 5.0 mmol scale.

图式3. 化合物1'与杂环化合物(2)的交叉偶联反应的底物适用性考察a

Scheme 3. Investigation of substrate scope in the cross-coupling reaction of compound 1' with heterocycles (2) a Reaction conditions (unless otherwise specified): 1 (0.2 mmol, 1.0 equiv.), 2 (2.0 mmol, 10.0 equiv.), DMAP (2.0 equiv.), DMSO (1.0 mL), purple LED (410~415 nm 10 W), 30 ℃, 12 h; N.D.=Not detected. b Recovery ratio of heterocycles. c 48 h. d 1.5 mL of DMSO.

图式4. 氰基的衍生化研究a

Scheme 4. Derivatization study of the cyano group a Reaction conditions (unless otherwise specified): 3/4 (0.2 mmol, 1.0 equiv.), ZnCl2 (0.25 mmol, 1.25 equiv.), TMSN3 (0.4 mmol, 2.0 equiv.), iPrOH (1.0 mL), 95 ℃, 4 h.

图式5. 机理研究

Scheme 5. Mechanism research

图式6. 可能的反应机理

Scheme 6. Proposed mechanism

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