Formation of C(sp2)–C(sp3) Bonds Instead of Amide C–N Bonds from Carboxylic Acid and Amine Substrate Pools by Decarbonylative Cross-Electrophile Coupling

15 March 2023, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


Carbonheteroatom bonds, most often amide and ester bonds, are the standard method to link together two complex fragments be-cause carboxylic acids, amines, and alcohols are ubiquitous and the reactions are reliable. However, CN and CO linkages are often a metabolic liability because they are prone to hydrolysis. While C(sp2)–C(sp3) linkages are preferable in many cases, methods to make them require different starting materials or are less functional-group compatible. We show here a new, decarbonylative reaction that forms C(sp2)–C(sp3) bonds from the reaction of activated carboxylic acids (via 2-pyridyl esters) with activated alkyl groups derived from amines (via N-alkyl pyridinium salts) and alcohols (via alkyl halides). Key to this process is a remarkably fast, reversible oxidative addi-tion/decarbonylation sequence enabled by pyridone and bipyridine ligands that, under reaction conditions that purge CO(g), lead to a selective reaction. The conditions are mild enough to allow coupling of more complex fragments, such as those used in drug develop-ment, and this is demonstrated in the coupling of a typical Proteolysis Targeting Chimera (PROTAC) anchor with common linkers via CC linkages.


cross-electrophile coupling
C-C bond formation


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.