One-Pot Synthesis of N-Substituted Isoindolin-1-ones via Reductive Amination/Lactamization of Methyl 2-Formylbenzoate

doi:10.6023/cjoc202202022

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (8): 2456-2461.DOI: 10.6023/cjoc202202022 Previous Articles Next Articles

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邻甲酰基苯甲酸甲酯还原胺化/内酰胺化一锅法合成N-取代异吲哚-1-酮

张文生^a^,^*(), 李焱^b, 崔海燕^a, 苏小莉^a, 徐素鹏^a

a 济源职业技术学院冶金化工系河南济源 459000
b 焦作师范高等专科学校合成技术研究所河南焦作 454100

收稿日期:2022-02-19 修回日期:2022-04-08 发布日期:2022-05-17
通讯作者: 张文生
基金资助:
河南省科技攻关计划(212102310883); 河南省教育厅自然科学重点研究(21B150013); 济源职业技术学院自然科学重点研究(JZXY-2020-58)

One-Pot Synthesis of N-Substituted Isoindolin-1-ones via Reductive Amination/Lactamization of Methyl 2-Formylbenzoate

Wensheng Zhang^a(), Yan Li^b, Haiyan Cui^a, Xiaoli Su^a, Supeng Xu^a

a Department of Metallurgy and Chemical Engineering, Jiyuan Vocational and Technical College, Jiyuan, Henan 459000
b Institute of Synthetic Technology, Jiaozuo Normal College, Jiaozuo, Henan 454100

Received:2022-02-19 Revised:2022-04-08 Published:2022-05-17
Contact: Wensheng Zhang
Supported by:
Program for Science and Technology Development of Henan Province(212102310883); Key Natural Science Research Program of the Education Department of Henan Province(21B150013); Key Natural Scientific Research Projects of Jiyuan Vocational Technical College(JZXY-2020-58)

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Abstract

An efficient, one-pot synthesis of N-substituted isoindolin-1-ones by an aminative reduction/lactamisation sequence of methyl 2-formylbenzoate is introduced. The reaction process includes aminative reduction of o-phthalaldehydic acid methylesters with primary aryl or alkyl amines using NaBH₃CN and the following intramolecular nucleophilic N-attack on carbonyl carbon atom. For 4-substituted aromatic amines, alkyl amines and o-methylaniline, the transformation can be successfully completed in 1,2-dichloroethane at room temperature. For other 2-substituted aromatic amines, reflux in acetonitrile for 8 h in the presence of K₂CO₃ (2 equiv.) is needed. The reaction scopes were quite broad and up to 96% yield of diverse products was achieved.

Key words: N-substituted isoindolin-1-ones, aminative reduction, lactamisation, one-pot synthesis

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Wensheng Zhang, Yan Li, Haiyan Cui, Xiaoli Su, Supeng Xu. One-Pot Synthesis of N-Substituted Isoindolin-1-ones via Reductive Amination/Lactamization of Methyl 2-Formylbenzoate[J]. Chinese Journal of Organic Chemistry, 2022, 42(8): 2456-2461.

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Fig. & Tab. 6

Figure 1. Representative biologically active N-substituted isoindolin-1-ones

Scheme 1. Synthesis of N-substituted isoindolin-1-ones via reductive amination/lactamization of methyl 2-formylbenzoate

Entry	R²	Product 3	Yield^a/%
1	C₆H₅	3a	91
2	4-MeC₆H₄	3b	96
3	4-MeOC₆H₄	3c	86
4	4-ClC₆H₄	3d	90
5	4-BrC₆H₄	3e	94
6	4-CNC₆H₄	3f	70
7	2-MeC₆H₄	3g	93
8	n-Bu	3h	88
9	t-Bu	3i	84
10	i-Pr	3j	85
11	Bn	3k	95
12		3l	95
13		3m	91
14		3n	61
15		3o	70

Table 1. Synthesis of N-4-substituted phenyl, N-2-methylphenyl and N-alkyl isoindolin-1-onesa

Entry	R²	Solvent	T/℃	Product 3	Yield^b/%
1	Cl	DCE	r.t.	3p	0
2	Cl	DCE	90	3p	66
3	Cl	MePh	90	3p	71
4	Cl	THF	90	3p	70
5	Cl	MeCN	90	3p	90
6	Br	MeCN	90	3q	84
7	Et	MeCN	90	3r	87

Table 2. Synthesis of N-2-substituted phenyl isoindolin-1-onesa

Scheme 2. Scope of methyl 2-formylbenzoates Reaction condition: methyl 2-formylbenzoate 1b~1d (0.5 mmol), amine 2b (0.525 mmol), DCE (5 mL), NaBH3CN (0.75 mmol), r.t., 12 h

Scheme 3. Gram-scale of reaction of 1a Reaction condition: methyl 2-formylbenzoate 1a (8 mmol), amine 2v (1.05 equiv.), DCE (10 mL), NaBH3CN (1.5 equiv.), r.t., 12 h

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邻甲酰基苯甲酸甲酯还原胺化/内酰胺化一锅法合成N-取代异吲哚-1-酮

One-Pot Synthesis of N-Substituted Isoindolin-1-ones via Reductive Amination/Lactamization of Methyl 2-Formylbenzoate

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