Heterocycle–Heterocycle Strategy for 4,5-Disubstituted Pyrrolidine 2,3-Diones: Reductive Rearrangement Approach from Isoxazole Esters

Abstract

The work demonstrates the heterocycle–heterocycle interconversion strategy to access 4,5-disubstituted 3-hydroxy-2-pyrrolidinone in moderate to good yields (50–80%). The approach has a distinct advantage over a multicomponent reaction approach as it allows access to unsubstituted 3-hydroxy-2-pyrrolidinone at the nitrogen position for further functionalization.

Key words

isoxazoles - pyrrolidinones - reductive rearrangement - heterocyle–heterocyle strategy - (3+2) cycloaddition - MCR

Publication History

Received: 10 April 2021

Accepted after revision: 27 April 2021

Accepted Manuscript online:
27 April 2021

Article published online:
10 May 2021

• References and Notes

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• 11 Prepared using the general procedure by starting with benzaldehyde oxime (3.0 mmol). Off-white solid, 71% yield; mp 62–64 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.71–7.70 (d, J = 7.3 Hz, 2 H), 7.54–7.46 (m, 3 H), 4.10 (s, 3 H), 3.92 (s, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 161.8, 161.2, 159.3, 156.4, 130.6, 128.8, 128.1, 126.8, 116.04, 53.3, 53.1 ppm. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₁NO₅: 261.0637; found: 261.0634.
• 12 General Procedure for the Synthesis of Pyrrolidine Diones 1a–lTo a solution of isoxazole ester (0.5 g) in acetic acid (5.0 mL) was added portionwise Fe powder (10.0 equiv.) at 100 °C. During the addition, the colorless solution turned to dark brown. The reaction was monitored by LC–MS and after complete conversion the reaction mass was cooled to RT and poured into saturated aqueous sodium bicarbonate solution (50.0 mL). The mixture was filtered over a bed of Celite and the filtrate was extracted with diethyl ether before acidification with concd HCl to pH 1. During acidification the color of the solution turned from pale yellow to red and colorless at pH 1. The product was extracted to ethyl acetate layer and concentrated to get target molecule as solid (50–80%).Methyl-4-hydroxy-5-oxo-2-phenyl-1,2-dihydropyrrole-3-carboxylate (1a)Prepared using the general procedure by starting with dimethyl 3-phenylisoxazole-4,5-dicarboxylate (3.0 mmol). Off-white solid, 71% yield; decomposes above 140 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.44 (s, 1 H), 9.27 (s, 1 H), 7.35–7.18 (m, 5 H), 5.18 (s, 1 H), 3.53 (s, 3 H) ppm. ¹³C NMR (101 MHz, DMSO-d ₆): δ = 166.3, 162.7, 154.2, 138.4, 128.3, 127.8, 127.1, 112.1, 56.4, 50.9 ppm. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₁NO₄: 233.0688; found: 233.0684.
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