Cu-Catalyzed Conjugate Addition of Grignard Reagents to Thiochromones: An Enantioselective Pathway for Accessing 2-Alkylthiochromanones

Abstract

The enantioselective incorporation of alkyl groups in thiochromones was realized for the first time by a Cu/(R,S)-PPF-P ^t Bu₂-catalyzed conjugate addition of Grignard reagents to thiochromones. With this method, a series of 2-methylthiochromanones were obtained in good yields (up to 96% yield) with moderate-to-good ee values (up to 87% ee). The established method expedites the synthesis of a large library of chiral thiochromanones for further synthetic applications and biological studies.

Key words

asymmetric synthesis - Grignard reagents - conjugate addition - thiochromanones - flavonoids

• References and Notes

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• 15 General Procedure for the Addition of Methylmagnesium Bromide to ThiochromonesAn oven-dried vial fitted with a stirring bar was charged with [Cu(MeCN)₄]PF₆ (3.73 mg, 5 mol%) and (R,S)-PPF-P ^t Bu₂ (6.51 mg, 6 mol%) in DCM (4.0 mL) and the mixture was stirred at rt for 30 min. Then, thiochromone 1a (0.20 mmol) was added and the mixture was then stirred at –75 °C for another 10 min. MeMgBr (0.30 mL, 0.30 mmol, 1.5 equiv; 1 M solution in THF) and iodotrimethylsilane (85 μL, 0.6 mmol, 3.0 equiv) were simultaneously added dropwise to the vial and the resulting mixture was stirred at –75 °C until the reaction was completed. The reaction was quenched with HCl aq (10%) and the mixture was stirred for 30 min at rt. Then, it was extracted with EtOAc and the organic layer was collected and concentrated under vacuum. The residue was purified by chromatography on silica gel (EtOAc/n-pentane 1:80) to obtain the desired products.6-Methoxy-2-methylthiochroman-4-one (3ba)Yellow liquid (29.8 mg, 72% yield). [α]_D ²⁵ = –59.320 (c 1.00, CH₂Cl₂). ee was determined to be 85% by HPLC analysis with a Chiralcel OJ-3 column (hexane/2-propanol 99.5:0.5, 1.0 mL/min, 254 nm); t _r (minor) = 36.8 min, t _r (major) = 44.6 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 2.9 Hz, 1 H), 7.18 (d, J = 8.7 Hz, 1 H), 7.03 (dd, J = 8.7, 2.9 Hz, 1 H), 3.84 (s, 3 H), 3.62 (dqd, J = 13.7, 6.8, 3.1 Hz, 1 H), 3.02 (dd, J = 16.6, 3.0 Hz, 1 H), 2.76 (dd, J = 16.5, 11.6 Hz, 1 H), 1.44 (d, J = 6.8 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.69, 157.40, 133.23, 131.16, 128.79, 122.50, 111.15, 55.57, 48.00, 36.68, 20.37 ppm. HRMS (ESI-ion trap): m/z: [M + H]⁺ calcd for C₁₁H₁₃O₂S: 209.0631; found: 209.0627.6-fluoro-2-methylthiochroman-4-one (3ia)Yellow liquid (38 mg, 96% yield). [α]_D ²⁵ = –85.050 (c 1.00, CH₂Cl₂). ee was determined to be 73% by HPLC analysis with a Chiralcel OJ-3 column (hexane/2-propanol 97:3, 1.0 mL/min, 254 nm); t _r (minor) = 9.0 min, t _r (major) = 9.8 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (dd, J = 9.3, 2.9 Hz, 1 H), 7.24 (dd, J = 8.7, 5.0 Hz, 1 H), 7.14 (ddd, J = 8.7, 7.8, 2.9 Hz, 1 H), 3.72–3.56 (m, 1 H), 3.02 (dd, J = 16.6, 3.0 Hz, 1 H), 2.75 (dd, J = 16.6, 11.6 Hz, 1 H), 1.44 (d, J = 6.8 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 193.82, 160.62 (d, J = 244 Hz), 137.10 (d, J = 3.0 Hz), 131.90 (d, J = 5.8 Hz), 129.39 (d, J = 6.9 Hz), 121.52 (d, J = 23 Hz), 115.13 (d, J = 22 Hz), 47.68, 36.76 20.44 ppm. HRMS (ESI-ion trap): m/z: [M + H]⁺ calcd for C₁₀H₁₀OFS: 197.0431; found: 197.0424.