Man Pan Leung, Pui Ying Choy, Wing In Lai, Kin Boon Gan, and Fuk Yee Kwong*
Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong—Org. Process Res. Dev. 2019, asap.
Recommended by Shi Li _ MOC
KEYWORDS: Phosphine, Arylation, Palladium, Sterically hindered, Cross-coupling
ABSTRACT: A practical scaled-up synthesis of a series of carbazolyl-derived phosphine ligands, the PhenCarPhos series, is described. The original protocol for accessing the target ligand skeleton via aromatic C−N bond formation is limited by the use of a substoichiometric amount of copper salt and diamine catalysts, which both add cost and generate purification problems. In order to develop a more attractive and scalable synthetic pathway, a simple nucleophilic substitution method was attempted involving simple heating of 1-bromo-2-fluorobenzene, a carbazole derivative, and KOH in DMF without inert atmosphere protection. This route enables the large-scale synthesis of the desired ligand skeletons and minimizes the association of inseparable reduction side products. Particular examples of the use of these ligands in Pd-catalyzed sterically hindered arylation processes are also shown.
Previous method:
Current method:
Applications of the Carbazolyl-Derived Phosphine Ligands:
Summary and Comments:
香港中文大學Kwong小組報導了一種方便經濟的咔唑芳基化方法製備PhCarPhos配體，並發現這類配體在大位阻Suzuki和Buchwald的偶聯反應中表現出優秀的反應活性。其發展的鹼性條件下咔唑與芳基氟化物的取代方法相較於之前所使用的銅催化/促進的方法不僅簡便經濟而且避免了脫滷副產物的生成，大量金屬殘留和柱層析分離。因此，我們認為該反應在藥物合成領域具有很好的應用前景。
Prof. Kwong etc reported a protocol for carbazole arylation using a nucleophilic aromatic substitution pathway with the features of being metal-free, requiring only an inexpensive base and avoiding column purification. This simple protocol was found to be scalable up to 100 g. The previous protocols of Cu-catalyzed/assisted C(sp2)−N bond construction processes need DMEDA ligand or a stoichiometric amount of Cu salt, leading to purification problem and formation of debrominated side product. And the carbazolyl-derived phosphine ligands were found to be able to efficiently promote arylation processes (10 g scale) using sterically hindered 2,6-disubstituted aryl chlorides as the representative electrophilic partners.