胺催化靛红与联烯酸酯的加成反应合成烯炔基-3-羟基氧化吲哚

doi:10.6023/cjoc202510023

摘要/Abstract

开发了一种高效构建具有潜在生物活性的烯炔型3-羟基氧化吲哚类化合物的新方法. 以三苯胺为有机催化剂, 碳酸钾为碱, 无水N,N-二甲基甲酰胺为溶剂, 室温即可实现靛红与β'-乙酰氧基联烯酸苄酯的加成反应, 合成了16个结构新颖的含烯炔结构的3-羟基氧化吲哚类化合物. 该方法具有反应条件温和、底物适用范围广和收率良好等显著优点, 为该类化合物的合成提供了高效途径. 克级实验进一步验证了该合成方法的实用性.

关键词: 胺催化, 靛红, β'-乙酰氧基联烯酸苄酯, 加成反应, 3-羟基氧化吲哚

An efficient synthetic methodology for constructing potentially bioactive enyne 3-hydroxyoxindole analogs was developed. The addition reaction between isatins and benzyl 2-(acetoxymethyl)buta-2,3-dienoate was successfully achieved under mild conditions using triphenylamine as an organocatalyst, potassium carbonate as base, and anhydrous N,N-dimethyl- formamide as solvent. This approach enabled the efficient synthesis of sixteen novel 3-hydroxyoxindole derivatives featuring conjugated enyne moieties. The developed protocol offers notable advantages, including mild reaction conditions, broad substrate scope, and excellent yields, thereby establishing a practical route for accessing this class of compounds. The applicability of the synthesis method was further verified by a gram-scale experiment.

Key words: amine catalyzed, isatins, benzyl 2-(acetoxymethyl)buta-2,3-dienoate, addition reaction, 3-hydroxyoxindole

引用此文

郭盼盼, 张雅博, 史雯赫, 陈良军, 郭冉. 胺催化靛红与联烯酸酯的加成反应合成烯炔基-3-羟基氧化吲哚[J]. 有机化学, 2026, 46(5): 2051-2058.

Panpan Guo, Yabo Zhang, Wenhe Shi, Liangjun Chen, Ran Guo. Amine-Catalyzed Addition Reaction of Isatins with Allenoates for the Synthesis of Enyne-Containing 3-Hydroxyoxindoles[J]. Chinese Journal of Organic Chemistry, 2026, 46(5): 2051-2058.

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图/表 7

图1. 含3-羟基氧化吲哚和共轭烯炔结构的代表性药物分子

Figure 1. Typical pharmaceutical molecules containing 3-hydroxyoxindole and conjugated enyne skeletons

图式1. 靛红与β'-乙酰氧基联烯酸苄酯的加成反应

Scheme 1. Addition reaction of isatins with benzyl 2-(acetoxymethyl)buta-2,3-dienoate

Entry	Catalyst	Solvent	Base	Yield^b/%
1^a	Et₃N	DMF	K₂CO₃	61
2	Et₃N	CH₃CN	K₂CO₃	50
3	Et₃N	Toluene	K₂CO₃	n.r.
4	Et₃N	CH₂Cl₂	K₂CO₃	20
5	Et₃N	CHCl₃	K₂CO₃	30
6	Et₃N	THF	K₂CO₃	n.r.
7	Et₃N	DMSO	K₂CO₃	20
8	Et₃N	DMF	Cs₂CO₃	Trace
9	Et₃N	DMF	Na₂CO₃	42
10	Et₃N	DMF	KHCO₃	52
11	Et₃N	DMF	CH₃COOK	49
12	Et₃N	DMF	DBU	Trace
13	Et₃N	DMF	DABCO	29
14	DMAP	DMF	K₂CO₃	Trace
15	DBU	DMF	K₂CO₃	Trace
16	DABCO	DMF	K₂CO₃	Trace
17	DIPEA	DMF	K₂CO₃	72
18	Ph₃N	DMF	K₂CO₃	80
19^c	Ph₃N	DMF	K₂CO₃	79
20^d	Ph₃N	DMF	K₂CO₃	Trace
21^e	Ph₃N	DMF	K₂CO₃	75

表1. 靛红(1a)与β'-乙酰氧基联烯酸苄酯(2)的加成反应条件筛选

Table 1. Screening of addition reaction conditions for isatin (1a) and benzyl 2-(acetoxymethyl)buta-2,3-dienoate (2)

图式2. 靛红1与β'-乙酰氧基联烯酸苄酯2的加成反应的底物适用性考察

Scheme 2. Investigation of substrate scope in the addition reaction of isatins 1 with benzyl 2-(acetoxymethyl)buta-2,3-dienoate 2 Reaction conditions: isatin (1, 0.5 mmol), benzyl 2-(acetoxymethyl)buta-2,3-dienoate (2, 0.75 mmol), K2CO3 (0.5 mmol), Ph3N (0.10 mmol), temperature (25 ℃).

图式3. 靛红1a与β'-乙酰氧基联烯酸苄酯2的加成反应的克级实验

Scheme 3. Gram-scale experiment of addition reaction of isatin and benzyl 2-(acetoxymethyl)buta-2,3-dienoate

图式4. 可能的反应机理

Scheme 4. Proposed mechanism

图式5. 反应中间体B的验证

Scheme 5. Verification of reaction intermediate B

参考文献 29

[1]	Baur S.; Hazra A.; Laha J. K.; Manna S. Green Chem. 2025, 27, 5442. doi: 10.1039/D5GC00780A
[2]	Kumar A.; Chimni S. S. RSC Adv. 2012, 2, 9748. doi: 10.1039/c2ra21131a
[3]	Liu Y.; Zhu F.; Wang C.; Zhou J. Chin. J. Org. Chem. 2013, 33, 1595 (in Chinese). doi: 10.6023/cjoc201303038
	(刘运林, 朱锋, 王翠红, 周剑, 有机化学, 2013, 33, 1595.) doi: 10.6023/cjoc201303038
[4]	Lv Y.; Wang Y.; Pu W.; Zhu X.; Wu N.; Zhao Y. Org. Chem. Front. 2020, 7, 2752. doi: 10.1039/D0QO00826E
[5]	Zhou Y.; Zhang Y.; Wang J. Org. Biomol. Chem. 2016, 14, 6638. doi: 10.1039/C6OB00944A
[6]	Xie B.-Y.; He Z.-T. ACS Catal. 2024, 14, 9742. doi: 10.1021/acscatal.4c02377
[7]	Gu J.; Li X.; Zhang Y.; Sun Z.; Li L.; Meng J.; Xing R.; Shi X.; Fu Y.; Wang L.; Guo R. J. Org. Chem. 2024, 89, 2364. doi: 10.1021/acs.joc.3c02377
[8]	Hajinasiri R. Tetrahedron 2022, 126, 133053. doi: 10.1016/j.tet.2022.133053
[9]	Zhang Y.; Chen J.; Yao H.; Wang Y.; Liu H.; Wang L.; Huang N.; Wang N. Chin. J. Chem. 2025, 43, 995. doi: 10.1002/cjoc.v43.9
[10]	Ji X.; Li Z.; Zhang J.; Zhang Y.; Meng L.-G. Chin. J. Chem. 2023, 41, 3031. doi: 10.1002/cjoc.v41.22
[11]	Zhang Q.; Yang L.; Tong X. J. Am. Chem. Soc. 2010, 132, 2550. doi: 10.1021/ja100432m
[12]	Han X.; Yao W.; Wang T.; Tan Y. R.; Yan Z.; Kwiatkowski J.; Lu Y. Angew. Chem. Int. Ed. 2014, 53, 5643. doi: 10.1002/anie.v53.22
[13]	Ziegler D. T.; Riesgo L.; Ikeda T.; Fujiwara Y.; Fu G. C. Angew. Chem. Int. Ed. 2014, 53, 13183. doi: 10.1002/anie.201405854 pmid: 25287684
[14]	Gu Y.; Hu P.; Ni C.; Tong X. J. Am. Chem. Soc. 2015, 137, 6400. doi: 10.1021/jacs.5b03273
[15]	Dai Z.; Zhu J.; Wang J.; Su W.; Yang F.; Zhou Q. Adv. Synth. Catal. 2020, 362, 545. doi: 10.1002/adsc.v362.3
[16]	Tang X.; Tan C. X. A.; Chan W.-L.; Zhang F.; Zheng W.; Lu Y. ACS Catal. 2021, 11, 1361. doi: 10.1021/acscatal.0c05225
[17]	Tang X.; Ni H.; Lu Y. Org. Chem. Front. 2021, 8, 4485. doi: 10.1039/D1QO00669J
[18]	Ni C.; Liang Z.; Xu X.; Yu F.; Zhang D.; Chen C. J. Org. Chem. 2024, 89, 4784. doi: 10.1021/acs.joc.4c00011
[19]	Li C.; Zhang Q.; Tong X. Chem. Commun. 2010, 46, 7828. doi: 10.1039/c0cc01966f
[20]	Li K.; Hu J.; Liu H.; Tong X. Chem. Commun. 2012, 48, 2900. doi: 10.1039/c2cc30242j
[21]	Ni C.; Tong X. J. Am. Chem. Soc. 2016, 138, 7872. doi: 10.1021/jacs.6b04935
[22]	Ni C.; Wang M. L.; Tong X. Org. Lett. 2016, 18, 2240. doi: 10.1021/acs.orglett.6b00874
[23]	Ni C.; Zhang Y.; Hou Y.; Tong X. Chem. Commun. 2017, 53, 2567. doi: 10.1039/C6CC09788J
[24]	Ni C.; Pan S.; Yuan C.; Qin S. J. Org. Chem. 2023, 88, 8937. doi: 10.1021/acs.joc.3c00679
[25]	Qureshi A. A.; Kumar A. S.; Swamy K. C. K. Adv. Synth. Catal. 2024, 366, 1165. doi: 10.1002/adsc.v366.5
[26]	Choe Y.; Lee P. H. Org. Lett. 2009, 11, 1445. doi: 10.1021/ol9001703
[27]	Zhang Q.; Jin H.; Feng J.; Zhu Y.; Jia P.; Wu C.; Huang Y. Org. Lett. 2019, 21, 1407. doi: 10.1021/acs.orglett.9b00130
[28]	Chen Z.; Xiong D.; Wang N.; Zhang Y.; Yao H.; Zhang J.; Huang N.; Zou K. Org. Chem. Front. 2024, 11, 2762. doi: 10.1039/D4QO00169A
[29]	Zhu Y.; Wang D.; Huang Y. Org. Lett. 2019, 21, 908. doi: 10.1021/acs.orglett.8b03819