Synlett 2017; 28(19): 2624-2628
DOI: 10.1055/s-0036-1588532
letter
© Georg Thieme Verlag Stuttgart · New York

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

Beatriz C. Calvo
Stratingh Institute for Chemistry, Nijenborgh 7, 9747 AG Groningen, The Netherlands   Email: a.j.minnaard@rug.nl
,
Stratingh Institute for Chemistry, Nijenborgh 7, 9747 AG Groningen, The Netherlands   Email: a.j.minnaard@rug.nl
› Author Affiliations
Financial support from The Netherlands Organization for Scientific Research (NWO-CW) is acknowledged.
Further Information

Publication History

Received: 09 June 2017

Accepted after revision: 10 July 2017

Publication Date:
17 August 2017 (eFirst)

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.

Supporting Information

 
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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. NH4Claq 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.