Decarbonylative Cross-Electrophile Coupling: Synthesis Of C–C Bonds Instead of C–N Bonds from Carboxylic Acids and Amines

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 metabol-ic liability because they are prone to hydrolysis. While C(sp2)–C(sp3) linkages are preferable in many cases, methods to make them re-quire 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-pyridyl esters) with activated 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 addi-tion/decarbonylation sequence enabled by 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 anchor with common linkers via C–C linkages.

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

“…30 The yield was improved by using 1.5 equiv of the alkyl pyridinium salt (entry 9). Besides ketone, the majority of the aryl mass balance was Ar− H. (16,20,27) aryl and heteroaryl carboxylic acid esters worked similarly well. The coupling of aryl carboxylic acid 2-pyridyl esters with electrophiles derived from amines (N-alkyl pyridinium salts) and from alcohols (alkyl bromides and iodides) works comparably for primary alkyl groups, but alkyl iodides give the best results with secondary alkyl groups (25,29,30,32).…”