Facile Synthesis of Isoindolinones via Radical-Mediated Intramolecular Coupling of Two C–H Bonds

Shuxiong Han; Shuo He; Zhibin Huang; Yingsheng Zhao; Gong Chen

doi:10.1055/a-2043-4862

Synlett, Table of Contents

Synlett 2023; 34(12): 1457-1461
DOI: 10.1055/a-2043-4862

cluster

Special Issue Honoring Masahiro Murakami’s Contributions to Science

Facile Synthesis of Isoindolinones via Radical-Mediated Intramolecular Coupling of Two C–H Bonds

Shuxiong Han

^aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. of China

,

Shuo He

^aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. of China

,

Zhibin Huang

^aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. of China

,

Yingsheng Zhao∗

^aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. of China

,

Gong Chen∗

^bState Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, P. R. of China

› Author Affiliations

Abstract

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Abstract

A metal-free method for the construction of 3,3-dimethyl isoindolinones via radical-mediated intramolecular coupling of two C–H bonds of N,N-diisopropyl benzamides was developed. The reactions can proceed in moderate to high yield and with excellent chemoselectivity. A reaction sequence of the formation of an alkyl radical via oxidative cleavage of alkyl C–H bond and the formation of lactam ring via intramolecular homolytic aromatic substitution was proposed.

Key words

C–H activation - isoindolinone - homolytic aromatic substitution - alkyl radical - benzamide

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References

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15 Representative Procedure for Isoindolone Synthesis The mixture of benzamide 1a (41.0 mg, 0.2 mmol), (NH₄)₂S₂O₈ (91.3 mg, 0.4 mmol), AcOH (34.4 μL, 0.6 mmol), and MeCN (1.0 mL) was sealed in a 15 mL glass vial under Ar with a ground-glass-type stopper. The reaction mixture was then stirred at 120 °C for 12 h before cooling to room temperature and being concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 10/1 to 5/1) to give the isoindolinone product 2a as a white solid (27.2 mg, 68%). ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (d, J = 7.5 Hz, 1 H, ArH), 7.52–7.48 (m, 1 H, ArH), 7.42–7.38 (m, 1 H, ArH), 7.34 (d, J = 7.5 Hz, 1 H, ArH), 3.70–3.60 (m, 1 H, CH), 1.56 (d, J = 6.9 Hz, 6 H, CH₃), 1.48 (s, 6 H, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 167.4, 151.4, 132.1, 131.4, 128.0, 123.4, 120.7, 63.4, 44.7, 25.6, 20.6. HRMS: m/z calcd for C₁₃H₁₇NNaO [M + Na]⁺: 226.1202; found: 226.1207.

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