镍催化氟代烯基硼酯与烷基卤化物Suzuki偶联反应

doi:10.6023/A18080333

摘要/Abstract

有机化合物特定位点嵌入氟原子或含氟片段，可以产生独特的生物或物理性质改变.单氟取代烯基是生物医药领域理想的酰胺键替代物，在医药化学、药物研发等方向已经获得广泛的应用.通过溴化镍（Ⅱ）二乙二醇二甲醚复合物、4，4'-二叔丁基-2，2'-二吡啶的催化体系，实现了多种氟代烯基硼酯与一级烷基卤化物碘代物、溴代物以及二级烷基溴代物的Suzuki偶联反应.该反应具有良好的收率和优秀的官能团兼容性，能够兼容酯基、氰基、醇羟基等多种具有有机合成化学价值的官能团，为单氟取代烯烃的合成提供了方法.机理实验表明该反应可能经历烷基卤化物自由基均裂历程.

关键词: 镍, 氟代烯基硼酯, 烷基卤化物, Suzuki偶联反应, 氟代烯烃

The incorporation of fluorine atoms or fluorine-containing fragments to specifical sites of organic compounds would result in unique diversifications in biological or physical properties, such as, significantly regulate the lipid solubility or metabolic stability, and promote specific binding ability to biological targets of target compounds. Monofluoroalkenes are ideal amide bond mimics, and have been widely used in the research field of pharmaceutical chemistry and drug discovery. Previously, we reported the nickel-catalyzed reductive cross coupling of gem-difluoroalkenes with unactivated secondary alkyl iodides and tertiary alkyl bromides. However, only medium yield can be obtained with primary alkyl halides, which might be caused by the lower stability and nucleophilic activity of these substrates. Herein, we report the nickel-catalyzed Suzuki-type cross coupling of fluorinated alkenyl boronates with alkyl halides for the synthesis of primary alkyl group substituted monofluoroalkenes. By using NiBr₂(diglyme) (10 mol%) and 4,4'-di-tert-butyl-2,2'-bipyridine (15 mol%) as catalytic systems, Na₂CO₃ (2 equiv.) as base, N,N-dimethylacetamide as solvent, we achieved the cross coupling of a variety of fluorinated alkenyl boronates with primary alkyl iodides (e.g., 5), bromides (e.g., 9) and relatively inert secondary alkyl bromide (20). Under the mild reaction conditions, this reaction performed smoothly with good isolated yields and well functional group toleration. Many synthetically useful functional groups could survive during the transformation, such as, ether (6, 7), trifluoromethyl (8), cyano (10), ester (11), and even unprotected alcohol hydroxyl group (13). In addition, heterocycles such as tetrahydrofuran (14), phthalimide (15), dioxane (16), indole (17), pyridine (27) and quinoline (35) also posed no problem for this reaction. It should be pointed out that, this reaction is applicable not only to non-activated alkyl halides, but also to the conversion of activated allyl bromides (18, 19). For the fluorinated alkenyl boronates, this reaction also exhibited good functional group compatibility and wide substrate scope, and conducted successfully with both electron-rich (e.g., 4, 24), electron-neutral (e.g., 21), or electron-deficient (e.g., 27, 31) aromatic rings. Finally, the toleration of aryl sulfonate (30) provided further opportunities for subsequent modification through transition-metal-catalyzed cross coupling reactions. Radical clock experiment with (Z)-8-iodooct-3-ene (36) provided a mixture of linear product (37a) and ring-cyclized product (37b). (Bromomethyl)cyclopropane (38) was also subjected to the standard reaction conditions, only ring-opening product (39a) was obtained. In addition, this reaction was significantly inhibited with the addition of TEMPO (2,2,6,6-tetramethylpiperidinooxy). These results indicated a radical-type reaction mechanism for the cross coupling of fluorinated alkenyl boronates with alkyl halides. Further efforts would be devoted to develop one-pot synthesis of monofluoroalkenes through in-situ borylation of gem-difluoroalkenes and subsequent Suzuki-type cross coupling with alkyl halides.

Key words: nickel, fluorinated alkenyl boronate, alkyl halides, Suzuki-type cross-coupling, fluorinated olefin

引用此文

何世江, 皮静静, 李炎, 陆熹, 傅尧. 镍催化氟代烯基硼酯与烷基卤化物Suzuki偶联反应[J]. 化学学报, 2018, 76(12): 956-961.

He Shijiang, Pi Jingjing, Li Yan, Lu Xi, Fu Yao. Nickel-Catalyzed Suzuki-Type Cross Coupling of Fluorinated Alkenyl Boronates with Alkyl Halides[J]. Acta Chim. Sinica, 2018, 76(12): 956-961.

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