Facile assembly of carbazolyl-derived phosphine ligands and their applications in palladium-catalyzed steric hindered arylation processes

Palladium-catalyzed cross-coupling reaction constitutes an important role in both academic and industrial areas of research especially in the pharmaceutical, natural product and agricultural syntheses. It allows the formation of carbon-carbon bond or carbon-heteroatom bond in the presence of transition metal catalyst. Indeed, the crosscoupling for carbon-heteroatom bond formation is particularly important. Many crucial basic building blocks of natural products and biologically active molecules contain carbon-heteroatom bond.¹⁻²In the previous studies, carbazolyl-derived phosphine ligands showed superior effects on sterically hindered coupling. Sterically hindered tri-ortho-substituted and tetraortho substituted biaryl compounds were able to be synthesized using carbazolylderived phosphine ligands.³⁻⁴In this thesis, a new series of carbazolyl-derived phosphine ligands is described. A wide range of carbazolyl-derived phosphine ligands with different substituents were prepared and investigated. The original synthetic scheme for accessing target ligand skeleton via aromatic C-N bond formation is limited by the use of sub-stoichiometric amount of copper salt and diamine catalysts, which both add cost and generate purification problems (significant amount of side products and copper residues). We herein report a more attractive and scalable synthetic pathway for large scale synthesis of the carbazolyl-derived phosphine ligand. This synthetic route exhibits the features of metal-free, requiring only inexpensive base (e.g. KOH), and avoiding using chromatographic purification. This simple protocol was found to be scalable up to 100 grams without difficulties, in which it enlightens the attractiveness of this tunable ligand family.⁵The newly developed carbazolyl-derived phosphine ligands have been applied in palladium-catalyzed sterically hindered N-arylation reactions for evaluating their efficacy. The phosphine ligand bearing an ortho-ethoxy group L7 at the carbazole ring gave a superior performance in the Pd-catalyzed sterically hindered Buchwald- Hartwig amination. The catalyst loading was able to be lowered to 0.03 mol% of Pd(OAc)₂. A wide range of tetra-ortho-substituted diarylamines were synthesized smoothly with excellent product yields.⁶ Not only the C-N bond-forming process, particular examples of employing these ligand systems in Pd-catalyzed sterically hindered carbon-carbon bond formation process were also demonstrated with good-to- excellent yield.⁵鈀催化的交叉偶聯反應在學術和工業研究領域都發揮著重要作用，特別是在藥物、天然產物和農業合成領域。在過渡金屬催化下，可生成碳-碳鍵或碳-雜原子鍵。 實際上，碳-雜原子鍵形成的交叉偶聯特別重要，天然產物和生物活性分子中許多重要的基本結構都含有碳－雜原子鍵。¹⁻²根據以往的研究發現，咔唑基衍生物的膦配體於高位阻偶聯反應中顯示出優異的效果，尤其它可用於合成具有位阻的三鄰位取代和四鄰位取代的聯芳基化合物。³⁻⁴此論文提出了一系列新的咔唑基衍生物膦配體。在研究中我們合成了大量具有不同取代基的咔唑基衍生物膦配體。在原本的合成途徑中，形成芳族碳-氮鍵以達成目標配體骨架受到亞化學計量的銅鹽和二胺催化劑的限制，這既增加了成本又產生了提純問題（生成大量副產物和銅殘留物）。 為解決以上問題，我們開發了更具吸引力和可擴張的合成途徑，以用於大規模合成咔唑基衍生物的膦配體上。新的合成路線無須添加金屬催化，僅需要加入廉價的鹼（例如氫氣化鉀）便能合成所需化合物，這合成方法更無需使用色譜柱層析來進行純化過程。這簡化的合成方法可擴展到用於100 克以內的規模，我們相信能大大提升此可調配體的吸引力。⁵新開發的咔唑基衍生膦配體其後應用於鈀催化的高位阻氮-芳基化反應上。 其中，在咔唑環上帶有鄰乙氧基L7 的膦配體在鈀催化的高位阻Buchwald–Hartwig偶聯反應中具有出色的功效。其中，鈀催化劑用量更可以降至0.03 mol％。這些配體可以順利合成各種四鄰位取代的二芳基胺，而且產品收率非常優異。⁶ 另外，它們還可應用於鈀催化的高位阻碳－碳鍵形成的過程中，產品收率良好至優異。⁵Lai, Wing In.M.Phil. Chinese University of Hong Kong 2020.Includes bibliographical references (leaves 91-94).Abstracts also in Chinese.Title from PDF title page (viewed on July 7, 2022)