Nature Chemistry
Nature Chemistry
9 months ago

Organocatalytic aromatization-promoted umpolung reaction of imines

Organocatalytic aromatization-promoted umpolung reaction of imines
Ye-Hui Chen, Meng Duan, Si-Li Lin, Yu-Wei Liu, Jun Kee Cheng, Shao-Hua Xiang, Peiyuan Yu, Kendall N. Houk, Bin Tan
The umpolung functionalization of imines bears vast synthetic potential, but polarity inversion is less efficient compared with the carbonyl counterparts. Strong nucleophiles are often required to react with the N-electrophiles without catalytic and stereochemical control. Here we show an effective strategy to realize umpolung of imines promoted by organocatalytic aromatization. The attachment of strongly electron-withdrawing groups to imines could enhance the umpolung reactivity by both electronegativity and aromatic character, enabling the direct amination of (hetero)arenes with good efficiencies and stereoselectivities. Additionally, the application of chiral Brønsted acid catalyst furnishes (hetero)aryl C–N atropisomers or enantioenriched aliphatic amines via dearomative amination from N-electrophilic aromatic precursors. Control experiments and density functional theory calculations suggest an ionic mechanism for the umpolung reaction of imines. This disconnection expands the options to forge C–N bonds stereoselectively on (hetero)arenes, which represents an important synthetic pursuit, especially in medicinal chemistry.

Publisher URL: https://www.nature.com/articles/s41557-023-01384-x

DOI: 10.1038/s41557-023-01384-x

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