Photocatalytic hydrogen atom transfer-induced Arbuzov-type -C(sp3)-H phosphonylation of aliphatic amines

09 August 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Despite remarkable progress in photocatalytic hydrogen atom transfer (HAT)-induced C(sp3)-H functionalization, achieving C(sp3)-H to C(sp3)-P transformation by the HAT process remains highly challenging due to P-reagents’ compatibility issues. α-Aminophosphonic acids have shown great potential in medicinal chemistry, yet their synthesis is hindered by limited substrate scopes, poor functional group tolerance, and reliance on pre-functionalized substrates, restricting their broad applications. Herein, we report a photocatalytic HAT-induced α-C(sp3)-H phosphonylation of aliphatic amines, providing rapid access to structurally diverse α-amionphosphonates from abundant amines. Leveraging intramolecular HAT, radical polar crossover, and Arbuzov-type phosphonylation cascade, the challenges associated with HAT-induced C(sp3)-H to C(sp3)-P transformation were overcome. This protocol features base-free, redox-neutral, mild conditions, broad scopes, and employing amines as limiting reagents, and allows for late-stage phosphonylation of complex drug molecules possessing amine moieties.

Keywords

Hydrogen atom transfer
photocatalysis
phosphonylation
α-aminophosphonates

Supplementary materials

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