A general Pd-catalyzed pathway to β-lactams

In a recent Science paper the Gaunt group reports facile access to β-lactams via palladium-catalyzed coupling of aliphatic amines and carbon monoxide. The scope of the reaction is remarkably broad; over 40 substrates are illustrated, bearing a wide range of substitution patterns and functional groups. The extensive functional group tolerance of the catalyst enables late-stage functionalization, which is a powerful synthesis strategy to allow rapid access to diverse amine-containing pharmaceutical agents.

Dispersion corrected DFT (BLYP-D3) calculations with ADF were central to unraveling the reaction mechanism. The calculations suggested that the migration of a carboxylate ligand onto a palladium bound carbonyl could form a palladium anhydride intermediate, which reacts with the amine to provide a palladium carbamoyl complex. This palladium carbamoyl complex then undergoes C(sp3)-H activation to provide a palladacycle, which yields the β-lactam product after reductive elimination.

Pd cartalyzed CO amine coupling

You have already subscribed to our newsletter. Thank you! If you don't receive our newsletters, email us.

D. Willcox, B.G.N. Chappell, K.F. Hogg, J. Calleja, A.P. Smalley, and M.J. Gaunt, A general catalytic β-C–H carbonylation of aliphatic amines to β-lactams, Science 354 851-857 (2016).

Key concepts