Enantioselective Reductive N-Cyclization-Alkylation Reaction of Alkene-Tethered Oxime Esters and Alkyl Iodides by Nickel Catalysis
Xue-Gong Jia, Qi-Wei Yao and Xing-Zhong Shu*
*College of Chemistry and Chemical Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou 730000, China,
Email: shuxingzh
lzu.edu.cn
X.-G. Jia, Q.-W. Yao, X.-Z. Shu, J. Am. Chem. Soc., 2022, 144, 13461-13467.
DOI: 10.1021/jacs.2c05523
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Abstract
Asymmetric cross-electrophile difunctionalization of tethered alkenes is a powerful tool for the production of chiral cyclic scaffolds. An enantioselective aza-Heck cyclization/cross-coupling sequence proceeds with primary, secondary, and a few tertiary alkyl iodides, to provide highly enantioenriched pyrrolines with improved molecular diversity under mild conditions.
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proposed mechanism
Details
The document discusses a novel enantioselective reductive N-cyclization−alkylation reaction of alkene-tethered oxime esters with alkyl iodides using nickel catalysis. This method represents a significant advancement in the field of asymmetric cross-electrophile difunctionalization of alkenes, particularly for the synthesis of chiral nitrogen heterocycles, which are crucial in pharmaceuticals and natural products. The reaction employs newly defined pyridinebis(oxazoline) ligands, resulting in highly enantioenriched pyrrolines with improved molecular diversity under mild conditions. The study highlights the potential of heterocyclization for accessing new chiral architectures, addressing a long-standing challenge in synthetic chemistry. The reaction is compatible with primary, secondary, and some tertiary alkyl iodides, and tolerates various functional groups, allowing for further structural modifications. The optimized conditions involve Ni(PCy3)2Cl2, ligand L16, 1,8-naphthyridine, and Zn in a mixed solvent of MeCN/DMF. The document also details the mechanistic insights and control experiments that support the proposed catalytic cycle, involving enantioselective migratory insertion and radical processes. This work opens new avenues for the development of asymmetric aza-Heck and cross-coupling sequences, contributing to the broader scope of asymmetric cross-electrophile difunctionalization of alkenes.
Key Words
ID: J48-Y2022
