Three-Component Reaction of 2-Formylbenzoic Acid, Primary Amines, and Fluorinated Malonates: An Efficient Approach to Fluorinated Isoindolin-1-ones

doi:10.6023/cjoc202603024

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (10): 4050-4055.DOI: 10.6023/cjoc202603024 Previous Articles Next Articles

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基于2-甲酰基苯甲酸、伯胺和氟代丙二酸酯的三组分反应: 合成含氟异吲哚啉-1-酮的有效方法

郑伟, 张文生^*(), 苏小莉, 杜新玲, 刘改云

济源职业技术学院材料工程学院河南省金属材料精细化开发及资源循环利用工程技术研究中心河南省金属材料精细化开发及资源循环利用工程技术研究中心河南济源 459000

收稿日期:2026-03-18 修回日期:2026-05-15 发布日期:2026-06-15
通讯作者: 张文生
基金资助:
河南省教育厅自然科学重点研究计划(25B150039); 济源市科技攻关计划(24023016)

Three-Component Reaction of 2-Formylbenzoic Acid, Primary Amines, and Fluorinated Malonates: An Efficient Approach to Fluorinated Isoindolin-1-ones

Wei Zheng, Wensheng Zhang^*(), Xiaoli Su, Xinling Du, Gaiyun Liu

Henan Province Engineering Technology Research Center of Refinement and Resource Recycling of Metal Materials, School of Materials Engineering, Jiyuan Vocational and Technical College, Jiyuan, Henan 459000

Received:2026-03-18 Revised:2026-05-15 Published:2026-06-15
Contact: Wensheng Zhang
Supported by:
Key Natural Science Research Program of Education Department of Henan Province(25B150039); Science and Technology Research and Development Program of Jiyuan City(24023016)

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Abstract

A one-pot, metal-free three-component reaction has been developed for the synthesis of fluorinated isoindolin-1-one derivatives at room temperatures. This method employs readily available 2-formylbenzoic acids, primary amines, and fluorinated dialkyl malonates. The reaction takes place smoothly in a mild system of ethanol at room temperature, avoiding metal contamination of the products. The transformation proceeds via a sequential condensation/Michael addition/in situ lactamization process, efficiently constructing the isoindolin-1-one core while precisely introducing a fluorine atom in one step to enhance the drug-likeness of the target products. Furthermore, a malonate ester functionality is introduced, providing convenience for further structural diversification of the molecules. The reaction exhibits good functional group compatibility with a variety of aromatic and aliphatic amines, and electron-rich aromatic amines as well as benzylamine derivatives afford the corresponding 3-(fluoromalonate)-substituted isoindolin-1-ones in moderate to excellent yields (up to 90%). This metal-free, mild-condition multicomponent strategy provides a direct and versatile new approach for constructing structurally diverse fluorinated bioactive compound libraries based on the privileged isoindolin-1-one scaffold.

Key words: isoindolin-1-one, three-component reaction, fluorination, lactamization, synthesis

Cite this article

Wei Zheng, Wensheng Zhang, Xiaoli Su, Xinling Du, Gaiyun Liu. Three-Component Reaction of 2-Formylbenzoic Acid, Primary Amines, and Fluorinated Malonates: An Efficient Approach to Fluorinated Isoindolin-1-ones[J]. Chinese Journal of Organic Chemistry, 2026, 46(10): 4050-4055.

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Entry	Solvent	T/℃	t/h	Yield^b/%
1	EtOH	r.t.	5	55
2	EtOH	80	5	57
3	EtOH	r.t.	12	79
4	EtOH	r.t.	30	79
5	DCM	r.t.	12	41
6	MeCN	r.t.	12	51
7	THF	r.t.	12	43
8	DMF	r.t.	12	57

Entry	Solvent	T/℃	t/h	Yield^b/%
1	EtOH	r.t.	5	55
2	EtOH	80	5	57
3	EtOH	r.t.	12	79
4	EtOH	r.t.	30	79
5	DCM	r.t.	12	41
6	MeCN	r.t.	12	51
7	THF	r.t.	12	43
8	DMF	r.t.	12	57

Entry	X	R¹, 2	R²	t/h	Product 4	Yield^b/%
1	H	Ph, 2a	Me	12	4a	79
2	H	4-MeC₆H₄, 2b	Me	12	4b	81
3	H	4-MeOC₆H₄, 2c	Me	12	4c	82
4	H	4-ClC₆H₄, 2d	Me	24	4d	Trace
5	H	2-MeC₆H₄, 2e	Me	24	4e	Trace
6	H	n-Bu, 2f	Me	12	4f	68
7	H	c-Hex-CH₂, 2g	Me	12	4g	71
8	H	Bn, 2h	Me	12	4h	81
9	H	4-MeBn, 2i	Et	12	4i	87
10	H	2-MeBn, 2j	Me	12	4j	61
11	H	4-ClBn, 2k	Et	12	4k	77
12	H	4-MeOBn, 2l	Et	12	4l	90
13	H	CH₂CO₂Et, 2m	Me	24	4m	0
14	Cl	2n	Me	12	4n	73

Entry	X	R¹, 2	R²	t/h	Product 4	Yield^b/%
1	H	Ph, 2a	Me	12	4a	79
2	H	4-MeC₆H₄, 2b	Me	12	4b	81
3	H	4-MeOC₆H₄, 2c	Me	12	4c	82
4	H	4-ClC₆H₄, 2d	Me	24	4d	Trace
5	H	2-MeC₆H₄, 2e	Me	24	4e	Trace
6	H	n-Bu, 2f	Me	12	4f	68
7	H	c-Hex-CH₂, 2g	Me	12	4g	71
8	H	Bn, 2h	Me	12	4h	81
9	H	4-MeBn, 2i	Et	12	4i	87
10	H	2-MeBn, 2j	Me	12	4j	61
11	H	4-ClBn, 2k	Et	12	4k	77
12	H	4-MeOBn, 2l	Et	12	4l	90
13	H	CH₂CO₂Et, 2m	Me	24	4m	0
14	Cl	2n	Me	12	4n	73

Compound	4a	4b	4c	4f	4g	4h	4i	4j	4k	4l
¹³C NMR (δ) of CF(COR²)₂	91.8	92.8	92.8	94.4	94.3	95.0	95.4	97.3	94.3	95.5
J_C-F/Hz	210.1	211.2	211.3	205.9	206.5	204.9	201.6	206.7	201.6	201.2

基于2-甲酰基苯甲酸、伯胺和氟代丙二酸酯的三组分反应: 合成含氟异吲哚啉-1-酮的有效方法

Three-Component Reaction of 2-Formylbenzoic Acid, Primary Amines, and Fluorinated Malonates: An Efficient Approach to Fluorinated Isoindolin-1-ones

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