A Catalyst-Free One-Pot Protocol for the Construction of Substituted Isoindolinones under Sustainable Conditions

Abstract

An operationally simple, one-pot, catalyst-free method was developed for the synthesis of pharmaceutically important substituted isoindolinones by a three-component reaction of 2-formylbenzoic acid, a primary amine, and a 1,3-dione in ethanol under dielectric heating.

Key words

isoindolinones - medicinal chemistry - multicomponent reaction - formylbenzoic acid - amines - diones

• References and Notes

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• 19 3-(2-Hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-2-(4-tolyl)isoindolin-1-one (10a); Typical Procedure A mixture of 2-formylbenzoic acid (7; 1.0 mmol), p-toluidine (8a; 1.0 mmol), and dimedone (9b; 1.0 mmol) in EtOH (1 mL) was stirred for 1 min and then subjected to microwave irradiation at 90 °C for 15 min. When the reaction was complete, the mixture was filtered and the product was dried to give a white solid; yield: 0.333 g (0.92 mmol, 92%); mp 264–266 °C; IR (KBr): 3404, 2922, 1622, 1206, 1095 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.72 (d, J = 7.4 Hz, 1 H), 7.44 (t, J = 7.4 Hz, 1 H), 7.35 (t, J = 7.4 Hz, 1 H), 7.28 (d, J = 7.8 Hz, 2 H), 7.21 (d, J = 7.4 Hz, 1 H), 7.04 (d, J = 7.9 Hz, 2 H), 6.43 (s, 1 H), 2.27 (d, J = 16.6 Hz, 1 H), 2.20 (s, 3 H), 2.09 (d, J = 16.6 Hz, 1 H), 2.01 (d, J = 16.8 Hz, 1 H), 1.84 (d, J = 16.9 Hz, 1 H), 0.89 (s, 3 H), 0.49 (s, 3 H). ¹³C NMR (75 MHz, pyridine-d ₅): δ = 190.2, 183.6, 169.4, 148.0, 138.2, 135.4, 134.9, 133.1, 130.6, 129.0, 124.4, 123.8, 123.6, 111.1, 57.6, 49.2, 47.9, 33.2, 29.7, 28.6, 22.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₄NO₃: 362.1751; found: 362.1730.
• 20 CCDC 1460875 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 21 Isoindolo[1,2-b][1,3]benzothiazol-11(4bH)-one (11); Typical Procedure A mixture of 2-formylbenzoic acid (7, 1.0 mmol) and 2-aminobenzenethiol (1.0 mmol) in EtOH (1 mL) was stirred for 1 min then subjected to microwave irradiation at 90 °C for 15 min. When the reaction was complete (TLC), the excess EtOH was evaporated under reduced pressure and the residue was purified by column chromatography [silica gel, MeOH–CH₂Cl₂ (2:98)] to give a white solid; yield: 0.200 g (0.84 mmol, 84%); mp 173–175 °C. IR (KBr): 3404, 2922, 1622, 1206, 1095 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 7.94 (d, J = 7.3 Hz, 1 H), 7.68–7.63 (m, 2 H), 7.60–7.53 (m, 2 H), 7.22–7.16 (m, 2 H), 7.11–7.06 (m, 1 H), 6.99 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.5, 143.1, 136.6, 135.9, 133.2, 132.7, 129.9, 125.9, 125.9, 125.2, 123.6, 123.1, 118.5, 69.2. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₀NOS: 240.0478; found: 240.0474.