A Computational Mechanistic Study of Cp*Co(III)-Catalyzed Three-Component C-H Bond Addition to Terpenes and Formaldehydes: Insights into the Origins of Regioselectivity.

Transition metal-catalyzed three-component reactions of arenes, dienes, and carbonyls enable the convergent synthesis of homoallylic alcohols. Controlling regioselectivity is a central challenge for the difunctionalization of substituted 1,3-dienes in which multiple unbiased C═C bonds exist. Here, the mechanisms of Cp*Co(III)-catalyzed three-component C-H bond addition to terpenes and formaldehydes were investigated by density functional theory calculations. The reaction proceeds via sequential C(sp2)-H activation, migratory insertion, β-hydride elimination, hydride reinsertion, and C-C bond formation to yield the final product. The migratory insertion is the rate- and regioselectivity-determining step of the overall reaction. We employed an energy decomposition approach to quantitatively dissect the contributions of different types of interactions to regioselectivity. For the 2-alkyl substituted 1,3-dienes, the orbital interactions in the 3,4-insertion are intrinsically more favorable as compared to that in the 4,3-insertion, while the stronger steric effects between metallacycle and 1,3-diene override the intrinsic electronic preference. However, the steric effects failed to rationalize the unfavorable 1,2-insertion that is analogous to 4,3-insertion and even bears smaller steric effects. The donor-acceptor interaction analysis indicates that orbital interactions between σCo-C and πC═C decreased significantly in the 1,2-insertion transition state, which leads to higher activation energy barriers. These insights into the dominant effects controlling regioselectivity will enable rational design of new catalysts for selective functionalization of dienes.