Photochemical 1,3-boronate Rearrangement Enables Three-component N-alkylation for α-tertiary Hydroxybenzylamine Synthesis

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Nov 26

PMID 39592574

Authors

Peng Zou

Dongmin Fu

Haoyang Wang

Ruoyu Sun

Yu Lan

Yiyun Chen

Affiliations

Soon will be listed here.

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.

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