Carbon heteroatom bonds, most often amide and ester bonds, are the standard method to link together two complex fragments, for example in PROTACs (proteolysis targeting chimeras), 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 and 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 O-2-pyridyl esters) with alkyl groups derived from amines (via N-alkyl pyridinium salts) and alcohols (via alkyl halides). The key to this process is a remarkably fast, reversible oxidative addition/decarbonylation sequence enabled by the pyridone and bipyridine ligands that, under conditions that purge CO(g) from the reaction, 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 PROTAC anchors with common linkers via C–C linkages.

Editing out the amide from amide-bond formation: Synthesis Of C–C bonds instead of C–N bonds from carboxylic acids and amines

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