Development and Mechanism of Rh-Catalyzed Keto-(5 + 1 + 2) Reaction of Keto-Vinylcyclopropanes and CO, and Answering Why Rh-Catalyzed Keto-(5 + 2) Reaction of Keto-Vinylcyclopropanes Fails.

Under Rh catalysis, ene-vinylcyclopropanes (ene-VCPs) can give (5 + 2) products or (5 + 2 + 1) products when CO is present. How about replacing the C2 synthon of the alkene in ene-VCPs with a carbonyl group? Can the resulting substrates, keto-vinylcyclopropanes (keto-VCPs), undergo either a keto-(5 + 2) or keto-(5 + 2 + 1) reaction in the presence of CO? Experimentally, the keto-(5 + 2) reaction failed, while the latter reaction succeeded, but via a keto-(5 + 1 + 2) reaction pathway, which has broad scope and can be applied to synthesize challenging eight-membered lactones. Quantum chemical calculations revealed that the keto-(5 + 1 + 2) reaction begins with VCP opening (an uphill process) followed by a rate-determining CO insertion (a downhill process), generating an allylic Rh species in a nearly thermodynamically neutral process. Then, an unexpected metallo-ene reaction of the allylic Rh species toward the carbonyl group occurs, followed by reductive elimination to furnish the final (5 + 1 + 2) cycloadducts. In contrast, if the keto-(5 + 2) reaction were to occur , it would need to overcome two uphill processes: the VCP opening (producing allylic Rh species) in an endergonic way (by 17 kcal/mol), and the metallo-ene reaction of the η1-allylic Rh species with the carbonyl group (the rate-determining step), with an overall activation free energy of 36.4 kcal/mol. Direct C═O insertion into the Rh-C bond is very difficult and cannot happen due to the strong π bond of the keto group compared to the π bond of the alkene. These kinetic and thermodynamic insights are useful for guiding the future design of transition metal-catalyzed reactions using ketones as two-atom synthons, which have been explored only to a limited extent so far.