Redox-Tag-Guided Radical Cation Diels–Alder Reactions: Use of Enol Ethers as Dienophiles

Abstract

Although radical cation Diels–Alder reactions enable the formation of cyclohexene ring systems between electronically mismatched (both electron-rich) dienes and dienophiles, which is otherwise difficult or impossible to achieve under thermal conditions, the substrate scope has been limited. Herein, we disclose that a radical cation Diels–Alder reaction using an enol ether as an electron-rich (and therefore oxidizable) dienophile is possible through a rationally designed redox tag strategy. Electrochemical and TiO₂ photochemical approaches are effective in driving the reaction, where both intermolecular and intramolecular electron transfers are the key.

Key words

redox tag - radical cation - Diels–Alder reaction - enol ether - electrochemistry - photochemistry

Publication History

Received: 14 July 2023

Accepted after revision: 29 August 2023

Accepted Manuscript online:
29 August 2023

Article published online:
23 October 2023

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• 12 Electrochemical Radical Cation Diels–Alder Reactions; General Procedure The appropriate enol ether (0.20 mmol) and 2,3-dimethylbuta-1,3-diene (45.0 μL, 0.40 mmol) were added with stirring to a solution of 1.0 M solution of LiClO₄ in CH₃NO₂ (20 mL) at r.t. The mixture was then electrolyzed with stirring at 1.2 V vs Ag/AgCl using carbon felt electrodes (10 × 10 mm) in an undivided cell under Ar. The solution was then diluted with H₂O and extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. The reported yields were determined by GC/MS analysis. The residue was purified by column chromatography [silica gel, 0.40 mmol scale (2 batches), hexane–EtOAc (24:1)]. All the reactions gave the corresponding cycloadducts as cis/trans mixtures. 1-Methoxy-4-[2-(6-methoxy-3,4-dimethylcyclohex-3-en-1-yl)ethyl]benzene (7) Colorless oil; yield: 27.0 mg (0.0985 mmol, 49%). ¹H NMR (600 MHz, CDCl₃): δ = (major) 7.11 (d, J = 7.2 Hz, 2 H), 6.83–6.81 (m, 2 H), 3.78 (s, 3 H), 3.42 (dt, J = 4.6, 2.3 Hz, 1 H), 3.31 (s, 3 H), 2.68–2.48 (m, 2 H), 2.31–2.20 (m, 1 H), 2.13–2.04 (m, 1 H), 1.96–1.91 (m, 2 H), 1.77–1.74 (m, 2 H), 1.61–1.36 (m, 7 H); (minor): 7.11 (d, J = 7.2 Hz, 2 H), 6.83–6.81 (m, 2 H), 3.78 (s, 3 H), 3.35 (s, 3 H), 3.15 (dt, J = 7.9, 5.5 Hz, 1 H), 2.68–2.48 (m, 2 H), 2.31–2.20 (m, 1 H), 2.13–2.04 (m, 1 H), 1.96–1.91 (m, 2 H), 1.77–1.74 (m, 2 H), 1.61–1.36 (m, 7 H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ = (major) 157.8, 135.1, 129.4, 124.9, 122.4, 113.8, 78.4, 56.5, 55.4, 36.6, 36.1, 35.1, 34.5, 32.8, 19.1, 18.9; (minor) 157.8, 135.2, 129.4, 124.7, 122.7, 113.9, 80.3, 57.0, 55.4, 38.0, 36.0, 34.2, 32.5, 32.1, 19.2, 19.1. HRMS (DART): m/z [M + H]⁺ calcd for C₁₈H₂₇O₂: 275.2006; found: 275.2005.
• 13 TiO₂ Photochemical Radical Cation Diels–Alder Reactions; General Procedure TiO₂ nanoparticles (100 mg) were added to a solution of the appropriate enol ether (0.20 mmol) and 2,3-dimethylbuta-1,3-diene (45.0 μL, 0.40 mmol) in a 1.0 M solution of LiClO₄ in CH₃NO₂ (4.0 mL). The mixture was stirred at r.t. 5 cm away from of a 15 W UV lamp (λ = 365 nm) under air. The solution was then diluted with H₂O and extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. The reported yields were determined by GC/MS analysis. The residue was purified by column chromatography [silica gel, 0.40 mmol scale (2 batches), hexane–EtOAc (24:1)]. All the reactions gave the corresponding cycloadducts as cis/trans mixtures.