Copper-catalyzed asymmetric allylic alkylation of racemic inert cyclic allylic ethers under batch and flow conditions

Jun Li; Xiao Song; Yan Wang; Junrong Huang; Hengzhi You; Fen-Er Chen

doi:10.1039/d3sc00127j

Copper-catalyzed asymmetric allylic alkylation of racemic inert cyclic allylic ethers under batch and flow conditions

Chem Sci. 2023 Mar 22;14(16):4351-4356. doi: 10.1039/d3sc00127j. eCollection 2023 Apr 26.

Authors

Jun Li¹, Xiao Song¹, Yan Wang¹, Junrong Huang^{1

2}, Hengzhi You^{1

2}, Fen-Er Chen^{1

2

3}

Affiliations

¹ School of Science, Harbin Institute of Technology (Shenzhen) Taoyuan Street, Nanshan District Shenzhen 518055 China hjunrong@hit.edu.cn youhengzhi@hit.edu.cn rfchen@fudan.edu.cn.
² Green Pharmaceutical Engineering Research Center, Harbin Institute of Technology (Shenzhen) Taoyuan Street, Nanshan District Shenzhen 518055 China.
³ Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University Shanghai 200433 China.

Abstract

Highly enantioselective Cu-catalyzed asymmetric allylic alkylation of racemic inert cyclic allylic ethers is accomplished in this work. The use of Grignard reagents in combination with BF₃·OEt₂ and CuBr·SMe₂/L2 is the key to enable employment of long-challenging low reactive allylic substrates in this AAA reaction. In addition, the approach exhibited a remarkable superiority in the construction of a stereogenic center involving challenging sterically hindered nucleophiles for both primary and secondary alkyl groups. Extension of this method under continuous flow conditions was also performed with excellent enantioselectivity in a short residence time. Mechanistic experiments indicated that the reaction proceeded through an in situ generated allylic bromide intermediate. All these advantages demonstrated that this chiral catalytic system is a valuable complement for existing asymmetric catalytic methods.