Asymmetric Intermolecular Conjugate Addition of 3-Substituted 2-Benzofuranones to Maleimides via Noncovalent NHC Catalysis

Abstract

An efficient N-heterocyclic carbene (NHC)-catalyzed asymmetric conjugate addition reaction to afford synthetically challenging benzofuranone derivatives having vicinal all-carbon quaternary and tertiary stereocenters is presented. The reaction operates solely through noncovalent interaction between a newly designed NHC and the substrates, providing access to a series of functionalized benzofuranones in good yields and with high ee values. The protocol applies to preparative-scale synthesis. A catalytic cycle involving a noncovalent substrate–NHC interaction is implicated in the process, based on a mechanistic control study.

Key words

asymmetric catalysis - N-heterocyclic carbenes - noncovalent interaction - conjugate addition - benzofuranones - maleimides

Publication History

Received: 22 July 2024

Accepted after revision: 26 August 2024

Accepted Manuscript online:
26 August 2024

Article published online:
27 September 2024

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• 20 General procedure: NHC-catalyzed intermolecular conjugate addition reaction to maleimides (GP-I):To a flame dried Schlenk tube equipped with a magnetic stir bar, azolium salt 1e (0.006 mmol, 3.0 mol%), activated 4 Å MS (30.0 mg) and toluene (1.5 ml) were added under Ar atmosphere. To the mixture, LiHMDS (1.0 M in THF, 0.004 mmol, 2.0 mol%) was added at 25 °C and the resulting mixture was stirred for 30 minutes. 3-Aryl-2-substituted benzofuranone (0.2 mmol, 1.0 equiv) and HFIP (0.002 mmol, 1.0 mol%) were then added to the mixture and stirring was continued for 10 minutes at 25 °C. The reaction mixture was then cooled to –78 °C and stirred for 10 minutes. To the cold mixture, a solution of appropriate maleimide (0.2 mmol, 1.0 equiv) in 0.5 mL toluene was added drop-wise under argon atmosphere. The reaction was continued for 12 h maintaining the reaction temperature at –78 °C. The reaction was quenched by adding 1.0 mL of water at –78 °C and the resulting mixture was stirred for 5 minutes. The reaction was allowed to warm to room temperature, organic layer was separated and aqueous layer was extracted with EtOAc (three times). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO₂, eluant: 25–40% EtOAc-PE) to afford the desired products. Compound 4: Prepared according to GP-I, combining 2a (42.0 mg, 0.2 mmol), 3a (34.6 mg, 0.2 mmol), 1e (3.7 mg, 0.006 mmol), LiHMDS (1.0 M in THF, 4.0 µL, 0.004 mmol), HFIP (0.2 µL, 0.002 mmol) and 4 Å MS (30.0 mg) in toluene (0.1 M, 2.0 mL) at –78 °C for 12 h. The crude product was purified by column chromatography (SiO₂, 30% EtOAc-PE, R_f = 0.3) to afford the product 4 in a mixture of diastereomers (62.0 mg, 82%, combined yield) as white solid. The diastereomeric ratio (dr) was determined to be 1:1 by ¹H NMR analysis.¹H NMR (500 MHz, CDCl₃) δ = 7.40–7.18 (m, 22 H, 11 H_major 11 H_minor), 7.10-7.09 (m, 2 H, 1 H_major , 1 H_minor), 6.66-6.64 (m, 2 H, 1 H_major , 1 H_minor), 4.29 (dd, J = 10.0, 4.5 Hz, 1 H_major ), 4.24 (dd, J = 9.5, 5.5 Hz, 1 H_minor), 3.02-2.92 (m, 2H, 1H_major , 1 H_minor), 2.71 (dd, J = 19.5, 4.5 Hz, 1 H_major ), 2.38 (dd, J = 18.5, 5.5 Hz, 1 H_minor) ppm.¹³ C NMR (125 MHz, CDCl₃) δ = 176.0, 175.8, 174.8, 174.3, 174.2, 173.5, 154.2, 153.6, 135.9, 135.6, 131.5, 131.2, 130.9, 130.7, 129.5, 129.3, 129.2, 129.1, 128.9, 128.9, 128.6, 127.5, 127.1, 126.5, 126.3, 126.2, 125.5, 125.5, 125.2, 124.7, 124.5, 112.4, 111.8, 56.3, 55.8, 55.7, 48.2, 46.4, 32.3, 32.2 ppm (additional 13C NMR signals are due to diastereomers).HRMS (ESI+) m/z calculated for C₂₄H₁₇NO₄ [M+H]⁺ 384.1236, found 384.1235. IR (Neat) V_max = 2923, 2852, 1797, 1714, 1478, 1388, 1132, 1069, 756, 696, 489 cm^–1.HPLC: The enantiomeric excess (86%) for both the diastereomers was determined by HPLC analysis using Daicel Chiralpak IG-3 column: n-hexane: i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τ_major = 17.25 min, τ_minor = 23.21 min for major diastereomer and τ_major = 32.16 min, τ_minor = 39.60 min for minor diastereomer.