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Synlett 2018; 29(15): 2071-2075
DOI: 10.1055/s-0037-1610225
DOI: 10.1055/s-0037-1610225
letter
Cu-Catalyzed Conjugate Addition of Grignard Reagents to Thiochromones: An Enantioselective Pathway for Accessing 2-Alkylthiochromanones
This work was supported by the Guangdong “Climbing” Program of China (Project No. pdjh2017c0023) and National 13th Five-year Key R&D Program of China (2016YFC0502607-01)
Further Information
Publication History
Received: 17 May 2018
Accepted after revision: 02 July 2018
Publication Date:
02 August 2018 (online)
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 - flavonoidsSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610225.
- Supporting Information
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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.