Copper-Catalyzed Asymmetric 1,2-Addition of Grignard Reagents to 3-Acyl 2H-chromenes

Abstract

Enones in which the carbon–carbon double bond is part of the pharmacologically important 2H-chromene (2H-1-benzopyran) nucleus undergo asymmetric copper-catalyzed 1,2-addition of Grignard reagents. High yields and enantiomeric excesses up to 84% are obtained and access to these novel enantio-enriched tertiary alcohols is provided.

Key words

asymmetric catalysis - Grignard reagents - copper catalysis - 1,2-addition - 2H-chromenes

• References and Notes

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• 23 General Procedure for the Enantioselective 1,2-Addition 1-[2-(2H-Chromen-3-yl)]-4-methylpentan-2-ol (14) To a flame-dried Schlenk tube containing a magnetic stirring bar, CuBr·SMe₂ (15 μmol, 3.1 mg), L1 (18 μmol, 10.7 mg), and 3 mL of dry t-BuOMe were added. The mixture was left to stir for 10 min. Subsequently, 9 (0.3 mmol, 52 mg) was added to the solution. The mixture was left to stir for 30 min at –78 °C. Isobutylmagnesium bromide (2 M in Et₂O, 1.7 equiv, 0.25 mL) was then added dropwise over 15 min, and the reaction was left to stir for 2 h at –78 °C. The reaction was quenched with H₂O (2 mL), allowed to warm up to r.t., and diluted with Et₂O. NH₄Cl_aq was added, and the layers were separated. The aqueous layer was extracted with Et₂O, and the combined organic layers were dried over MgSO₄, filtered, and concentrated at reduced pressure to afford 14 in 70% yield as a yellowish oil after flash chromato­graphy (SiO₂, n-pentane/Et₂O (90:10)); 80% ee. Retention times on chiral HPLC: t _R = 28.2 min and 31.8 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.11 (td, J = 7.5, 1.3 Hz, 1 H), 7.03 (dd, J = 7.4, 1.5 Hz, 1 H), 6.92–6.86 (m, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 6.46 (s, 1 H), 4.73 (d, J = 0.7 Hz, 2 H), 1.75 (m, 1 H), 1.57 (dd, J = 5.9, 2.2 Hz, 3 H), 1.40 (s, 3 H), 0.96 (t, J = 7.0 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 153.2, 134.0, 128.7, 126.8, 123.0, 121.5, 117.7, 115.4, 74.3, 65.6, 48.8, 28.0, 24.5, 24.5, 24.4. [α]_D ²⁰ –7.8 (c 1.0, CHCl₃). HRMS (ESI^–): m/z calcd for [C₁₅H₂₀O₂ – H]^–: 231.139; found: 231.138. Analytical Data for Compound 21 80% ee. Retention times on chiral HPLC: t _R = 13.2 min and 14.4 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.11 (td, J = 7.7, 1.7 Hz, 1 H), 7.04 (dd, J = 7.5, 1.6 Hz, 1 H), 6.90 (td, J = 7.4, 1.1 Hz, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 6.48 (s, 1 H), 4.63 (s, 2 H), 1.86–1.74 (m, 1 H), 1.64–1.46 (m, 5 H), 0.99 (d, J = 6.6 Hz, 3 H), 0.93 (d, J = 6.7 Hz, 3 H), 0.87 (t, J = 7.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 153.1, 138.1, 128.6, 126.7, 123.0, 121.5, 119.0, 115.4, 65.8, 47.9, 32.9, 24.6, 24.4, 24.2, 7.5. [α]_D ²⁰ +11.0 (c 1.0, CHCl₃). HRMS (ESI⁺): m/z calcd for [C₁₆H₂₂O₂ + H]⁺: 247.169; found: 247.169.