Issue 20, 2024

A HAT process of N-pyridyl radical cations for the synthesis of benzophenone-type bioisosteres

Abstract

N-Pyridyl radical cations are versatile synthetic intermediates, and interest in developing novel strategies for generating them and exploring their inherent reactivity is long-standing. Although Katritzky salts are powerful reagents for the generation of alkyl radicals via single-electron transfer and fragmentation, an alternative fragmentation pathway, that is, cleavage of the C–N bonds to afford alkyl radicals and nitrogen-centered pyridyl radical cations, would offer new synthetic opportunities and facilitate a process in N-pyridyl radical cation chemistry. In this study, we developed a photochemical method for generating alkyl radicals and N-pyridyl radical cations from Katritzky salts and reported the application of these radicals in novel functionalization reactions of [1.1.1]propellane to rapidly generate benzophenone-type bioisosteres. Mechanistic investigations indicate the light-induced, K2HPO4 promoted homolytic cleavage of the Katritzky salt C–N bond to produce an alkyl radical and an N-pyridyl radical cation and subsequent hydrogen atom transfer between the N-pyridyl radical cation and the aldehyde to generate an acyl radical. This mild method does not require a metal or photosensitizer and tolerates a broad range of functional groups. We demonstrated its utility by modifying a series of peptide feedstocks and drugs.

Graphical abstract: A HAT process of N-pyridyl radical cations for the synthesis of benzophenone-type bioisosteres

Supplementary files

Article information

Article type
Research Article
Submitted
20 Jul 2024
Accepted
21 Aug 2024
First published
26 Aug 2024

Org. Chem. Front., 2024,11, 5712-5719

A HAT process of N-pyridyl radical cations for the synthesis of benzophenone-type bioisosteres

Y. Wang, J. Dong, F. Li, C. Wang, X. Zhou, Q. Jiang, H. Liao, J. Dang, G. Li and D. Xue, Org. Chem. Front., 2024, 11, 5712 DOI: 10.1039/D4QO01338G

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