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Nickel-Catalyzed Asymmetric Addition of Aromatic Halides to Ketones: Highly Enantioselective Synthesis of Chiral 2,3-Dihydrobenzofurans Containing a Tertiary Alcohol

Ying Li, Wendian Li, Jiangyan Tian, Guozheng Huang* and Hui Lv*

*Xinjiang Technical Institute of Physics & Chemistry, Urumqi, Xinjiang 830011; Sauvage Center for Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China, Email: g.huangms.xjb.ac.cn, huilvwhu.edu.cn

Y. Li, W. Li, J. Tian, G. Huang, H. Lv, Org. Lett., 2020, 22, 5353-5357.

DOI: 10.1021/acs.orglett.0c01612


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Abstract

A highly enantioselective and straightforward intramolecular asymmetric addition of aryl halides to unactivated ketones provides chiral 3-hydroxy-2,3-dihydrobenzofurans with a chiral tertiary alcohol at the C-3 position in good yields and excellent enantioselectivities.

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Details

The document discusses a highly enantioselective synthetic procedure for chiral 3-hydroxy-2,3-dihydrobenzofurans using nickel/bisoxazoline-catalyzed intramolecular asymmetric addition of aryl halides to unactivated ketones. This method achieves up to 92% yield and 98% enantiomeric excess (ee). The reaction is significant as it avoids the use of moisture-sensitive and expensive organometallic reagents, providing a more straightforward approach to synthesizing chiral tertiary alcohols. The study highlights the challenges in achieving enantioselective addition to ketones and the effectiveness of various ligands and solvents in optimizing the reaction. The best results were obtained using Ni(PPh3)4 and bisoxazoline ligand L6 in i-PrOH solvent. The method was successfully applied on a gram scale without loss of yield or enantioselectivity. The reaction mechanism involves the formation of a chiral active species, followed by oxidative addition and intramolecular addition to generate the target product. This research offers a practical and efficient route to synthesize chiral 3-hydroxy-2,3-dihydrobenzofurans, which are important in natural products with biological activities. Further investigations on nickel-catalyzed asymmetric reactions are ongoing.


Key Words

2,3-Dihydrobenzofurans


ID: J54-Y2020