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

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• 作者：Vijay Singh ; Yoshiaki Nakao ; Shigeyoshi Sakaki ; Milind M. Deshmukh
• 刊名：Journal of Organic Chemistry
• 出版年：2017
• 出版时间：January 6, 2017
• 年：2017
• 卷：82
• 期：1
• 页码：289-301
• 全文大小：811K
• ISSN：1520-6904

文摘

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–AlMe₃ adduct with the active species Ni⁽⁰⁾(NHC)(C₂H₂) 1 in an η²-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)/AlMe₃ catalyst, the C⁴- and C³-alkenylated products (ΔG°^⧧ = 17.4 and 21.5 kcal mol^–1, respectively) are formed preferably to the C² one (ΔG°^⧧ = 22.0 kcal mol^–1). The higher selectivity of the C⁴-alkenylation over the C³ and the C² ones is attributed to the small steric repulsion between NHC and AlMe₃ in the C⁴-alkenylation. Interestingly, with Ni(P(i-Pr)₃)/AlMe₃ catalyst, the C²-alkenylation occurs more easily than the C³ and C⁴ ones. This regioselectivity arises from the smaller steric repulsion induced by P(i-Pr)₃ than by bulky NHC. It is notable that AlMe₃ accelerates the alkenylation by inducing the strong CT from Ni to pyridine–AlMe₃. In the absence of AlMe₃, pyridine strongly coordinates with the Ni atom through the N atom, which increases Gibbs activation energy (ΔG°^⧧ = ∼27 kcal mol^–1) of the C–H bond activation. In other words, AlMe₃ plays two important roles, acceleration of the reaction and enhancement of the regioselectivity for the C⁴-alkenylation.