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(sp(2))-H alkynylation of substrates with beta-carbolinamide and picolinamide as N,N-bidentate chelating groups on the basis of the identity of the TIPS alkyne halide coupling partner: TIPS alkyne bromides give delta-C(sp(2))-H alkynylation products while TIPS alkyne iodides give gamma-C(sp(2))-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 delta-palladation is kinetically favored over gamma-palladation, whereas the latter is thermodynamically favored. However, equilibration of the palladacycles makes them both accessible as reactive intermediates. TIPS alkyne bromides react selectively with the six-membered palladacycle (from delta-palladation) through a migratory insertion pathway. The observed delta-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 gamma-selectivity observed with TIPS alkyne iodides arises from a switch in mechanism, from migratory insertion to Pd(II)/Pd(IV) oxidative addition. Finally, an in-depth mechanistic study uncovered a beta-Pd effect, which is analogous to the well-established beta-Si effect, that promotes delta-C-H alkynylated product formation through an unusual vinyl beta-halo elimination.