Theoretical Study of Nickel-Catalyzed Selective Alkenylation of Pyridine: Reaction Mechanism and Crucial Roles of Lewis Acid and Ligands in Determining the Selectivity

Selective alkenylation of pyridine is challenging in synthetic organic chemistry due to the poor reactivity and regioselectivity of the aromatic ring. We theoretically investigated Ni-catalyzed selective alkenylation of pyridine with DFT. The first step is coordination of the pyridine–AlMe 3 adduct with the active species Ni (0) (NHC)(C 2 H 2 ) 1 in an η 2 -fashion to form an intermediate Int1 . After the isomerization of Int1, the oxidative addition of the C–H bond of pyridine across the nickel–acetylene moiety occurs via a transition state TS2 to form a Ni (II) (NHC) pyridyl vinyl intermediate Int3 . This oxidative addition is rate-determining. The next step is C–C bond formation between pyridyl and vinyl groups leading to the formation of vinyl-pyridine ( P1 ). One of the points at issue in this type of functionalization is how to control the regioselectivity. With the use of Ni(NHC)/AlMe 3 catalyst, the C 4 - and C 3 -alkenylated products (Δ G ° ⧧ = 17.4 and 21.5 kcal mol –1, respectively) are formed preferably to the C 2 one (Δ G ° ⧧ = 22.0 kcal mol –1 ). The higher selectivity of the C 4 -alkenylation over the C 3 and the C 2 ones is attributed to the small steric repulsion between NHC and AlMe 3 in the C 4 -alkenylation. Interestingly, with Ni(P( i -Pr) 3 )/AlMe 3 catalyst, the C 2 -alkenylation occurs more easily than the C 3 and C 4 ones. This regioselectivity arises from the smaller steric repulsion induced by P( i -Pr) 3 than by bulky NHC. It is notable that AlMe 3 accelerates the alkenylation by inducing the strong CT from Ni to pyridine–AlMe 3 . In the absence of AlMe 3, pyridine strongly coordinates with the Ni atom through the N atom, which increases Gibbs activation energy (Δ G ° ⧧ = ∼27 kcal mol –1 ) of the C–H bond activation. In other words, AlMe 3 plays two important roles, acceleration of the reaction and enhancement of the regioselectivity for the C 4 -alkenylation.