Metal-free Photocatalytic Cross-Electrophile Coupling enables C1 Homologation and Alkylation of Carboxylic Acids with Aldehydes

16 November 2023, Version 1


In contemporary drug discovery, enhancing the sp3-hybridized character of molecular structures is paramount, necessitating innovative synthetic methods. Herein, we introduce a deoxygenative cross-electrophile coupling technique that pairs easily accessible carboxylic acid-derived redox-active esters (RAEs) with aldehyde sulfonyl hydrazones, employing Eosin Y as an organophotocatalyst under visible light irradiation. This approach serves as a versatile, metal-free C(sp3)−C(sp3) cross-coupling platform. We demonstrate its synthetic value as a safer, broadly applicable C1 homologation of carboxylic acids, offering an alternative to the traditional Arndt-Eistert reaction. Additionally, our method provides direct access to cyclic and acyclic β-arylethylamines using diverse aldehyde-derived sulfonyl hydrazones. Notably, the methodology proves to be compatible with the late-stage functionalization (LSF) of peptides on solid-phase, streamlining the modification of intricate peptides without the need for exhaustive de-novo synthesis.


cross-electrophile coupling
C1 homologation
sp3-sp3 coupling
late-stage functionalization
peptide modification
flow chemistry

Supplementary materials

Supporting Information
Synthetic procedures, Experimental data, Spectroscopical analysis


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.