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

Prashantha Kamath; Vaibhav Jadhav; Mukul Lal

doi:10.1055/a-1492-8216

Synlett, Table of Contents

Synlett 2021; 32(11): 1146-1150
DOI: 10.1055/a-1492-8216

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

Prashantha Kamath

^aSyngenta Biosciences Pvt. Ltd. Santa Monica Works, Corlim, Ilhas, Goa 403110, India

^bDepartment of Chemistry, Mangalore University, Mangalagangothri, 574199, Karnataka, India

,

Vaibhav Jadhav

^aSyngenta Biosciences Pvt. Ltd. Santa Monica Works, Corlim, Ilhas, Goa 403110, India

,

Mukul Lal∗

^aSyngenta Biosciences Pvt. Ltd. Santa Monica Works, Corlim, Ilhas, Goa 403110, India

^bDepartment of Chemistry, Mangalore University, Mangalagangothri, 574199, Karnataka, India

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Abstract

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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

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References

References and Notes

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10 General Procedure for the Synthesis of Isoxazoles 6To a solution of oxime (1.0 mmol, 1.0 equiv.) in DMF (2.0 mL) at room temperature was added N-chlorosuccinimide (1.1 mmol, 1.1 equiv.) and stirred for 60 min. Dimethylacetylenedicarboxylate (DMAD) was added in one portion (1.1 mmol, 1.1 equiv.). Then, a solution of triethylamine (1.0 mmol, 1 equiv.) in DMF (1.0 mL) was added. The solution was stirred at RT till the reaction completes. The reaction mass poured into ice water, stirred for 10 min and extracted with ethyl acetate. The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and concentrated in vacuum. Purification if necessary was done by column chromatography using cyclohexane and ethyl acetate as mobile phase. §#BLD#§Dimethyl 3-Phenylisoxazole-4,5-dicarboxylate (6a)
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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