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, ß-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.

Mechanism and origins of ligand-controlled Pd(ii)-catalyzed regiodivergent carbonylation of alkynes.

Transition-metal-catalyzed carbonylation provides a useful approach to synthesize carbonyl-containing compounds and their derivatives. Controlling the regio-, chemo-, and stereoselectivity remains a significant challenge and is the key to the success of transformation. In the present study, we explored the mechanism and origins of the ligand-controlled regiodivergent carbonylation of alkynes with competitive nucleophilic amino and hydroxy groups by density functional theory (DFT) calculations. The proposed mechanism involves O(N)-cyclization, CO insertion, N-H(O-H) cleavage, C-N(C-O) reductive elimination and regeneration of the catalyst. The chemoselectivity is determined by cyclization. Instead of the originally proposed switch of competitive coordination sites, a new type of concerted deprotonation/cyclization model was proposed to rationalize the ligand-tuned chemoselectivity. The electron-deficient nitrogen-containing ligand promotes the flow of electrons during cyclization, and so it favors the O-cyclization/N-carbonylation pathway. However, sterically bulky and electron-rich phosphine controls the selectivity by a combination of electronic and steric effects. The improved mechanistic understanding will enable further design of selective transition-metal-catalyzed carbonylation.