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 bromides give δ-C­(sp2)–H alkynylation products while TIPS alkyne iodides 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 bromides 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 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 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.