Mechanism of Cobalt-Catalyzed Direct Aminocarbonylation of Unactivated Alkyl Electrophiles: Outer-Sphere Amine Substitution To Form Amide Bond

Experimentalists have recently achieved the first chemoselective aminocarbonylation of unactivated alkyl electrophiles, using the common cobalt reagent Co-2(CO)(8) as a catalyst. Here, we present a detailed density functional theory (DFT) mechanistic study on this remarkable reaction. Induced by the Lewis base morpholine (or MOR, the amine substrate), Co-2(CO)(8) disproportionates to [Co(CO)(3)(MOR)(2)](+) and [Co(CO)(4)](-). The active catalyst [Co(CO)(4)](-) undergoes an S(N)2 reaction with the alkyl tosylate substrate to form an alkylcobalt(I) carbonyl intermediate with an inverted configuration at the alpha-carbon. The alkylcobalt(I) carbonyl complex favors CO migratory insertion over beta-hydride elimination. The resulting acylcobalt(I) carbonyl intermediate, along with the MOR and CO substrates, could introduce several pathways for the amide C-N bond formation. The inner-sphere pathways involving Co(I)-bound MOR are ruled out. The outer-sphere pathway in which MOR attacks the Co(I)-bound acyl leads to the amide product and the regenerated [Co(CO)(4)](-). The S(N)2 process is the rate-determining step with the largest energy span (Delta G* = 22.8 kcal/mol). The side reaction of double CO insertion faces a higher selectivity-determining energy barrier and hence is less favorable. This DFT work provides deep mechanistic insights into the Co-2(CO)(8)-promoted chemoselective aminocarbonylation of unactivated alkyl electrophiles, thereby having implications for organocobalt catalysis and transition-metal-catalyzed amide C-N bond-forming reactions.