Study on Dearomatization [4＋2] Reactions of Allene Substrates

doi:10.6023/cjoc202509001

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (3): 941-950.DOI: 10.6023/cjoc202509001 Previous Articles Next Articles

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基于联烯类底物的去芳构化[4＋2]反应研究

秦永圳^a, 陈洋^a^,^b^,^*(), 何述钟^a^,^b^,^*(), 杨岚^a^,^b^,^*()

^a 贵州大学药学院贵阳 550025
^b 贵州省合成药物工程实验室贵阳 550025

收稿日期:2025-09-01 修回日期:2025-11-21 发布日期:2025-12-25
基金资助:
国家自然科学基金(22361008); 国家自然科学基金(82473814); 国家自然科学基金(22061008); 贵州省基础研究计划(ZK[2023]-097); 贵州省基础研究计划(MS[2025]-654)

Study on Dearomatization [4＋2] Reactions of Allene Substrates

Yongzhen Qin^a, Yang Chen^a^,^b^,^*(), Shuzhong He^a^,^b^,^*(), Lan Yang^a^,^b^,^*()

^a College of Pharmacy, Guizhou University, Guiyang 550025
^b Drug Synthetic Engineering Laboratory of Guizhou Province, Guizhou University, Guiyang 550025

Received:2025-09-01 Revised:2025-11-21 Published:2025-12-25
Contact: *E-mail: szhe@gzu.edu.cn; ychen1@gzu.edu.cn; yanglan20ty@163.com
Supported by:
National Natural Science Foundation of China(22361008); National Natural Science Foundation of China(82473814); National Natural Science Foundation of China(22061008); Guizhou Provincial Science and Technology Foundation(ZK[2023]-097); Guizhou Provincial Science and Technology Foundation(MS[2025]-654)

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Abstract

The bicyclic [2.2.2] octane skeleton is widely present in natural products with complex structures, and such compounds have attracted much attention due to the diversity of their biological activities. Therefore, how to construct the cage structure of such molecules is an important issue in drug synthesis. In this study, a class of dearomatization [4＋2] reactions of diene substrates were developed, and the construction of a dihydrofuran bicyclic [2.2.2] octane tricyclic skeleton was achieved. This project focuses on the [4＋2] reaction strategy based on benzene rings as dienes, and has developed a new type of dearomatization [4＋2] reaction for arylcycloalkoxy diene substrates. By employing accessible raw materials and catalyst-free conditions, this approach offers the advantages of mild reactions, environmental benignity, single-product selectivity, fewer synthetic steps, and high cost-effectiveness, with the [4＋2] reaction affording an excellent final yield. Compared with the reported dearomatization [4＋2] reaction of phenylcyclopropene substrates, this reaction is more straightforward. The construction of cycloaddition products was completed only under thermodynamic conditions without the use of a catalyst. Finally, the synthesis of compounds 2a~2r was completed, and the single crystal cultures of compounds 2e and 2f were carried out. The absolute configuration of the dihydrofuran bicyclic [2.2.2] octane tricyclic skeleton was determined through X-ray single crystal diffraction experiments. On this basis, the synthesis of 4a~4d was completed through Suzuki coupling reaction. Through bioactivity determination, it was found that compound 4a had half inhibitory activity on the in vitro tumor growth of leukemia HL-60, and its IC₅₀ value for leukemia HL-60 cells was (11.96±0.30) μmol/L. This then laid the foundation for the medicinal chemistry research of such complex tricyclic systems.

Key words: bicyclic [2.2.2] octane, [4＋2] reaction, allenes, dearomatization

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Yongzhen Qin, Yang Chen, Shuzhong He, Lan Yang. Study on Dearomatization [4＋2] Reactions of Allene Substrates[J]. Chinese Journal of Organic Chemistry, 2026, 46(3): 941-950.

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Fig. & Tab. 9

References 17

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Entry	Cat. (mol%)	Solvent (mL)	Temp./℃	Yield^b/%
1^c	LiBr	1,3,5-Trioxane, toluene (51.0)	90	0
2^c^,^d	LiI	1,3,5-Trioxane, toluene (51.0)	90	0
3^e	Au(PPh₃)NTf₂ (4)	Toluene (51.0)	90	0
4^e^,^f	Ph₃PAuCl (4)	Toluene (51.0)	90	0
5	—	Benzene (51.0)	80	0
6	—	Toluene (51.0)	100	82
7	—	Toluene (51.0)	110	85
8	—	Toluene (51.0)	120	80
9	—	Toluene (51.0)	130	78
10	—	Toluene (51.0)	140	76
11	—	Toluene (51.0)	150	74
12	—	Toluene (51.0)	160	72
13	—	Toluene (25.5)	100	79
14	—	Toluene (25.5)	110	83
15	—	Toluene (25.5)	120	75
16	—	Toluene (25.5)	130	73
17	—	Toluene (25.5)	140	70
18	—	Toluene (25.5)	150	68
19	—	Toluene (25.5)	160	65

Entry	Cat. (mol%)	Solvent (mL)	Temp./℃	Yield^b/%
1^c	LiBr	1,3,5-Trioxane, toluene (51.0)	90	0
2^c^,^d	LiI	1,3,5-Trioxane, toluene (51.0)	90	0
3^e	Au(PPh₃)NTf₂ (4)	Toluene (51.0)	90	0
4^e^,^f	Ph₃PAuCl (4)	Toluene (51.0)	90	0
5	—	Benzene (51.0)	80	0
6	—	Toluene (51.0)	100	82
7	—	Toluene (51.0)	110	85
8	—	Toluene (51.0)	120	80
9	—	Toluene (51.0)	130	78
10	—	Toluene (51.0)	140	76
11	—	Toluene (51.0)	150	74
12	—	Toluene (51.0)	160	72
13	—	Toluene (25.5)	100	79
14	—	Toluene (25.5)	110	83
15	—	Toluene (25.5)	120	75
16	—	Toluene (25.5)	130	73
17	—	Toluene (25.5)	140	70
18	—	Toluene (25.5)	150	68
19	—	Toluene (25.5)	160	65

Compd.	(Inhibition rate±SD)^a/%
Compd.	HL-60	A549	MDA-MB-231	SW480
2j	4.03±1.72	20.82±2.43	3.09±1.86	19.13±1.39
4a	87.81±1.05	43.22±1.75	46.88±3.73	35.92±2.03
4c	10.32±2.94	16.44±0.72	0.53±2.86	21.22±2.33
4d	15.30±5.10	24.93±0.76	9.11±1.05	26.63±0.55
DDP^b	93.37±2.06	78.71±1.36	71.99±1.56	80.66±1.66

Compd.	(Inhibition rate±SD)^a/%
Compd.	HL-60	A549	MDA-MB-231	SW480
2j	4.03±1.72	20.82±2.43	3.09±1.86	19.13±1.39
4a	87.81±1.05	43.22±1.75	46.88±3.73	35.92±2.03
4c	10.32±2.94	16.44±0.72	0.53±2.86	21.22±2.33
4d	15.30±5.10	24.93±0.76	9.11±1.05	26.63±0.55
DDP^b	93.37±2.06	78.71±1.36	71.99±1.56	80.66±1.66

Compd.	(Inhibition rate±SD)^a/%
4a	11.96±0.30
DDP^b	2.92±0.15

基于联烯类底物的去芳构化[4＋2]反应研究

Study on Dearomatization [4＋2] Reactions of Allene Substrates

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