Understanding Regiodivergence in a Pd(II)-Mediated Site-Selective C–H Alkynylation

Although C–H functionalization is now established as a powerful tool for chemical synthesis, achieving site selectivity can be challenging, especially in complex systems. Here, we report regiodivergence in a Pd­(II)-mediated C­(sp²)–H alkynylation of substrates with β-carbolinamide and picolinamide as N,N-bidentate chelating groups on the basis of the identity of the TIPS alkyne halide coupling partner: TIPS alkyne <i>bromides</i> give δ-C­(sp²)–H alkynylation products while TIPS alkyne <i>iodides</i> give γ-C­(sp²)–H alkynylation products. Using an integrated experimental and computational approach, we examine the C–H alkynylation mechanism and determine the factors leading to the observed selectivity in great detail. We show that δ-palladation is kinetically favored over γ-palladation, whereas the latter is thermodynamically favored. However, equilibration of the palladacycles makes them both accessible as reactive intermediates. TIPS alkyne <i>bromides</i> react selectively with the six-membered palladacycle (from δ-palladation) through a migratory insertion pathway. The observed δ-selectivity in this case is attributed to decreased ring strain in the migratory insertion transition state with the six-membered palladacycle. We demonstrate that the γ-selectivity observed with TIPS alkyne <i>iodides</i> arises from a switch in mechanism, from migratory insertion to Pd­(II)/Pd­(IV) oxidative addition. Finally, an in-depth mechanistic study uncovered a β-Pd effect, which is analogous to the well-established β-Si effect, that promotes δ-C–H alkynylated product formation through an unusual vinyl β-halo elimination