鎳金屬與雜芳基醚的碳氧鍵芳基化反應機制探討

Abstract

從天然來源衍生的芳基醚在過渡金屬催化交叉偶聯反應中，提供了一種可持續替代傳統芳基鹵化物的方法，其選擇性進行碳氧鍵活化的挑戰已在過去 40 年中得到解決。在此反應蓬勃發展下已經透過多位化學家經由理論計算和實驗佐證其反應機制。在這些成功研究的基礎上，科學家研究重點現已轉向生物活性分子，如雜芳基醚。雜芳基醚的碳氧鍵活化大部分針對了較容易斷鍵的芳基氨基磺酸鹽 (aryl sulfamate)、氨基甲酸酯 (carbamate)、碳酸鹽 (carbonate)，而甲氧基 (methoxy)也只專注鄰位的甲氧基吡啶進行研究。本實驗室也對於間位與對位的甲氧基吡啶的研究成果呈現了不佳的催化效果。首先我們分析了鄰位與對位甲氧基吡啶反應產率較差的原因 : (1) 吡啶衍伸物會與金屬進行氧化還原的協同作用 (MLC) (2) 吡啶衍生物會進行二聚化反應(MLRR)。在此，本論文報導了雜芳基醚的碳氧鍵芳基化反應中同時有兩種反應 : 碳氧鍵芳基化 (C–O arylation) 及自身偶聯 (homo–coupling) 的產物。為了瞭解這兩種個別的反應機制，我們設計實驗並以其結果進行機制驗證。首先為 C–O arylation 反應，甲氧基吡啶經由鎳催化進行了雙電子機制的氧化加成反應後再進行還原消去，可以得到碳氧鍵活化產物。但因其反應速度過快使得原位監測 x-ray 吸收光譜 (XAS)，無法取得實驗中完整的氧化還原過程。因此我們利用次級動力學同位素 (s–KIE) 實驗得到了碳氧斷鍵為反應中的速率決定步驟，再搭配理論計算結果推導出吡啶 C-O arylation 機制。在吡啶自由基 homo–coupling 反應則是經由 EPR 監測反應過程的單電子訊號獲得證實。另外，在反應過程中添加了自由基捕獲劑 (Radical scavengers) 參與反應並成功抑制了自身偶聯反應，經由實驗證實了單電子偶聯反應的路徑。此研究主要分析:(1)甲氧基吡啶於鎳金屬催化的交叉偶聯反應 (2) 金屬-配體氧化還原反應。同時優化了吡啶碳氧鍵芳基化催化效能並展示了芳基吡啶和聯吡啶的廣泛底物範圍的合成策略。

Aryl ethers derived from naturally occurring sources have garnered significant attention as sustainable alternatives to conventional aryl halides in transition metal-catalyzed cross-coupling reactions. While substantial progress has been made over the past four decades in the selective activation of carbon–oxygen (C–O) bonds—underpinned by both theoretical modeling and experimental validation—most advances have centered around electronically activated leaving groups such as aryl sulfamates, carbamates, and carbonates. In contrast, methoxy-substituted heteroaryl ethers, particularly meta- and para-substituted methoxypyridines, remain underexplored due to their low reactivity and mechanistic complexity.

In this thesis, a comprehensive investigation into the Ni-catalyzed C–O bond activation of methoxypyridines is presented. Our preliminary studies revealed poor catalytic efficiency for meta- and para-methoxypyridine substrates, which we attribute to two major challenges: (1) redox cooperativity between the pyridine core and the nickel catalyst, and (2) dimerization of the pyridine derivatives. To address these challenges and gain mechanistic insight, we examined two competing pathways observed during the reaction: C–O arylation and homo-coupling.

Mechanistic studies demonstrate that the C–O arylation proceeds via a two-electron oxidative addition of the methoxypyridine to a nickel(0) center, followed by reductive elimination to afford the desired arylated product. Due to the experiment of in situ X-ray absorption spectroscopy (XAS) was unable to capture intermediate redox states. To overcome this limitation, secondary kinetic isotope effect (s-KIE) experiments were employed and revealed that C–O bond cleavage constitutes the rate-determining step. These experimental observations were corroborated by density functional theory (DFT) calculations, which further elucidated the electronic landscape governing the transformation.

In parallel, the homo-coupling pathway was investigated and found to proceed through a single-electron transfer mechanism. The presence of pyridine radical intermediates was confirmed by electron paramagnetic resonance (EPR) spectroscopy. Additionally, the formation of homo-coupled byproducts was significantly suppressed upon the introduction of radical scavengers, validating the role of radical species in this competing pathway.

Collectively, this research provides critical mechanistic insights into the C–O bond activation of methoxypyridines and establishes a platform for controlling selectivity in nickel-catalyzed cross-coupling reactions. Furthermore, the optimized catalytic conditions developed herein enable the efficient synthesis of structurally diverse arylpyridines and bipyridines, demonstrating the broad substrate scope and synthetic utility of this methodology. These findings contribute to the advancement of sustainable cross-coupling strategies for heteroaryl ether functionalization and open new avenues for the design of bioactive molecule derivatives.