Understanding Reactivity and Stereoselectivity in Palladium-Catalyzed Diastereoselective sp3 C–H Bond Activation: Intermediate Characterization and Computational Studies

The origin of the high levels of reactivity and diastereoselectivity (>99:1 dr) observed in the oxazoline-directed, Pd­(II)-catalyzed sp3 C–H bond iodination and acetoxylation reactions as reported in previous publications has been studied and explained on the basis of experimental and computational investigations. The characterization of a trinuclear chiral C–H insertion intermediate by X-ray paved the way for further investigations into C–H insertion step through the lens of stereochemistry. Computational investigations on reactivities and diastereoselectivities of C–H activation of t-Bu- and i-Pr-substituted oxazolines provided good agreement with the experimental results. Theoretical predictions with DFT calculations revealed that C–H activation occurs at the monomeric Pd center and that the most preferred transition state for C–H activation contains two sterically bulky t-Bu substituents in anti-positions due to steric repulsion and that this transition state leads to the major diastereomer, which is consistent with the structure of the newly characterized C–H insertion intermediate. The structural information about the transition state also suggests that a minimum dihedral angle between C–H bonds and Pd–OAc bonds is crucial for C–H bond cleavage. We have also utilized density functional theory (DFT) to calculate the energies of various potential intermediates and transition states with t-Bu- and i-Pr-substituted oxazolines and suggested a possible explanation for the substantial difference in reactivity between the t-Bu- and i-Pr-substituted oxazolines.