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.

Abstract

Carbon-heteroatom bonds, most often amide and ester bonds, are the standard method to link together two complex fragments because carboxylic acids, amines, and alcohols are ubiquitous and the reactions are reliable. However, C-N and C-O 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 addition/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 development, and this is demonstrated in the coupling of a typical Proteolysis Targeting Chimera (PROTAC) anchor with common linkers via C-C linkages.