Transition Metal-Catalyzed Hydroaminocarbonylation of Alkenes and Alkynes

The amide is a cornerstone in pharmaceuticals and materials, yet its synthesis typically relies on stoichiometric reactions via functional group transformation. Transition-metal-catalyzed hydroaminocarbonylation of alkenes/alkynes with CO and amines offers complete atom economy, but long suffered from catalyst poisoning by basic amines and poor regioselectivity. In this Account, we summarize our group's systematic efforts to address these challenges through "basicity masking". Mechanistic studies revealed that aliphatic amines deactivate the key Pd-H species; thus, temporarily attenuating amine basicity-ultilizing weak acids, ammonium chloride, or in situ derivatization-enables catalytic turnover. This strategy permitted hydroaminocarbonylation with aliphatic amines, ammonium salt, and even tertiary amines or amides as nitrogen source. Excellent regioselectivity for linear or branched amides was achieved by ligand control. The approach was extended to intramolecular carbonylative cyclizations, providing atom-economical access to diverse lactams and N-heterocycles, including β-lactams and bridged polycycles. Recently, nickel catalysis could enable the hydroaminocarbonylation proceed at ambient conditions in enantioselective manner. These developments illustrate how mechanistic insight can transform a historically narrow reaction into a versatile, sustainable platform for amide and Nheterocycle synthesis.