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


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.

Version notes

Several new mechanistic experiments shed additional light on CO removal, additional information on functional-group compatibility, many improvements in writing and references.