Decoding the Selective Formation of One over Eight Possible Products in a Pd-Catalyzed Multicomponent Reaction

Abstract

We present a comprehensive mechanistic investigation of a Pd-catalyzed multicomponent reaction (MCR) involving diazoesters, allylic esters, and amines. Using state-of-the-art density functional theory (DFT) and the DLPNO–CCSD(T) method, we delineate the reaction landscape, in which up to eight products are theoretically accessible. Computed energetics rule out five pathways, while the remaining three are N–H inserted product, N-allylated product (two-component products), and the three-component product (allylated amino ester) reveal a finely balanced competition governed by both kinetic and thermodynamic factors. We show how subtle variations in base, solvent, and temperature modulate the reactivity of transient organometallic intermediates and the interplay between Pd carbene species and π-allyl Pd complexes, supported by control experiments. For the major three-component product, a relay mechanism operates wherein the kinetically driven N–H inserted product undergoes Cs2CO3-mediated deprotonation to generate a nucleophilic partner. Among the various nucleophilic species considered, Cs-enolate aggregates are established as the most probable nucleophile. The observed lack of asymmetric induction in such MCRs is attributed to the formation of E/Z geometric isomers of the Cs-enolate. This study underscores the importance of accurately defining the true nature of nucleophiles in carbene as well as (or involving) allylation chemistry, especially under one-pot conditions where multiple intermediates coexist.