Photochemical 1,3-boronate rearrangement enables three-component N-alkylation for α-tertiary hydroxybenzylamine synthesis

Peng Zou, Dongmin Fu, Haoyang Wang, Ruoyu Sun, Yu Lan () and Yiyun Chen ()
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Peng Zou: University of Chinese Academy of Sciences
Dongmin Fu: Zhengzhou University
Haoyang Wang: University of Chinese Academy of Sciences
Ruoyu Sun: University of Chinese Academy of Sciences
Yu Lan: Zhengzhou University
Yiyun Chen: University of Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Hydroxybenzylamines are prevalent in drugs and bioactive molecules, including various antimalarial and anticancer drugs. α-tertiary alkylation of amines impacts drug-target interactions significantly through their influence on basicity and lipophilicity. Traditional N-alkylation methods, especially for α-tertiary amines, suffer from limitations due to high energy barriers from steric hindrance. In this work, we leverage visible light irradiation to enable the organoboronic acid addition to sterically hindered ketimines in the excited state. Notably, it overcomes the limitations of the well-explored Petasis reaction, which is restricted to aldimines due to the high energy barrier associated with ketimines (51.3 kcal/mol). This three-component coupling of aliphatic amines, o-phenolic ketones, and organoboronic acids delivers diverse α-tertiary o-hydroxybenzylamines (77 examples, yields up to 82%) with broad functional group tolerance. The light-driven 1,3-boronate rearrangement introduces quaternary carbon centers adjacent to the amine moiety to enable late-stage functionalization of complex bioactive molecules. This versatile tool for complex amine synthesis holds significant potential for accelerating advancements in drug discovery, chemical biology, and materials science research.

Date: 2024
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DOI: 10.1038/s41467-024-54165-6

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