新型对硅胶稳定的芳基硼酸酯,并且Suzuki-Miyaura反应活性更高!

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2016年,Dean G. Brown等人在J. Med. Chem.期刊发表文章统计并分析了1984年和2014年各种 类型化学反应出现频率(1984年和2014年各选125篇来自J. Med. Chem. 的文章)。对比了20年来各种反应出现频率的变化趋势, 2014年排名前五名的反应类型:1)酰胺键形成反应,(2)SNAr反应,(3)Boc保护脱保护反应,(4)酯水解反应,(5) Suzuki−Miyaura偶联 。 J. Med. Chem. 2016, 59, 4443−4458 

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各种反应类型在最后一步的出现频率排行,中 Suzuki–Miyaura反应 也排在第二位,这足以说明 Suzuki–Miyaura反应 在药物合成中的重要性。

新型对硅胶稳定的芳基硼酸酯,并且Suzuki-Miyaura反应活性更高!  第2张

正因为其应用频率之高,因此用于反应的有机硼试剂,也在不断发展中。最新发现的就是2007年发现的 Burke硼酸试剂 。但是由于频哪醇硼酸酯易于合成,其应用范围最广。但是做过硼酸酯的小伙伴们都知道,反应监测时,体系非常干净,但是柱层析纯化后,大概率会有一部分产物变成硼酸, 频哪醇硼酸酯柱层析,非常容易拖尾,因此要得到纯度很高的硼酸酯非常困难。

新型对硅胶稳定的芳基硼酸酯,并且Suzuki-Miyaura反应活性更高!  第3张

近期,Naoki Oka等人报道了一种新型的芳基硼酸酯----芳基硼酸

1,1,2,2-四乙基乙二醇酯[ArB(Epin)s]。此类型硼酸酯非常适合利用硅胶柱层析进行纯化,而且分离产率非常高,克服了常规硼酸酯的分解和拖尾问题。利用 ArB(Epin)用于 Suzuki–Miyaura反应 产率也优于相应的芳基硼酸或芳基硼酸频哪醇酯。【 Org. Lett. 2022, 24, 19, 3510–3514

新型对硅胶稳定的芳基硼酸酯,并且Suzuki-Miyaura反应活性更高!  第4张

此试剂和硼酸频哪醇酯的合成方法类似,合成起来非常方便,可以通过芳基硼酸与 1,1,2,2-四乙基乙二醇进行酯化得到,也可以利用B2Epin2进行 Miyaura硼酸酯化反应 得到。

新型对硅胶稳定的芳基硼酸酯,并且Suzuki-Miyaura反应活性更高!  第5张

新型对硅胶稳定的芳基硼酸酯,并且Suzuki-Miyaura反应活性更高!  第6张

新型对硅胶稳定的芳基硼酸酯,并且Suzuki-Miyaura反应活性更高!  第7张

与频哪醇硼酸酯相比,此试剂的优点就对硅胶稳定,非常易于分离。

新型对硅胶稳定的芳基硼酸酯,并且Suzuki-Miyaura反应活性更高!  第8张

Suzuki–Miyaura反应 活性对比, ArB(Epin)也优于相应的芳基硼酸或芳基硼酸频哪醇酯

新型对硅胶稳定的芳基硼酸酯,并且Suzuki-Miyaura反应活性更高!  第9张

反应操作

A 100 mL flask was charged with tetrahydroxydiboron 0.38 g (4.2 mmol), Ethylpinacol 1.5 g (8.4 mmol) and potassium acetate 1.0 g (11 mmol) under N2 atmosphere, then it was diluted with toluene 40 mL, and refluxed for 16 h with a Dean-Stark apparatus. The reaction mixture was cooled to room temperature, filtered through Celite, concentrated under reduce pressure to gain 4,4,4’,4’,5,5,5’,5’-octaethyl-2,2’-bis(1,3,2-dioxabororan)[5a] as a colorless solid (1.5 g, 99%). Mp 62.7–64.5 °C. 1H NMR (300 MHz, CDCl3) δ: 1.75–1.60 (16 H, m), 0.90 (24 H, t, J = 7.5 Hz). 13C NMR (100 MHz, CDCl3) δ: 88.3, 26.4, 8.9.

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General Procedure I: A flask with a magnetic stir bar was charged with boronic acid 1 (1.0 equiv) and 3,4-diethylhexane-3,4-diol, Epin (1.0 equiv) and evacuated and back-filled with nitrogen. Anhydrous CH2Cl2 (0.10 M) was added to the flask via a syringe, and the mixture was stirred for 16 h at room temperature. After the reaction was quenched with H2O, the reaction mixture was extracted thrice with CH2Cl2. The combined organic phase was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (a mixture of hexane and EtOAc) to afford aryl boronic acid 3,4-diethylhexane-3,4-diol ester, ArB(Epin) 2.

General Procedure II: An oven-dried flask with a magnetic stir bar equipped with an inlet adapter with three-way stopcock was evacuated and back-filled with nitrogen. Aryl halide 3 (1.0 equiv) was charged in the flask and evacuated and back-filled with nitrogen. Anhydrous THF (0.10 M) was added to the flask via a syringe and cooled to –78 °C. 2.7 M n-BuLi in hexane [or 1.0 M i-PrMgCl·LiCl in THF or 1.6 M t-BuLi in pentane] (1.2 equiv) was added to the mixture at –78 °C via a syringe and the mixture was stirred for 1 h. After B(OMe)3 (2.0 equiv) was added to reaction mixture, the reaction mixture was allowed to warm up to room temperature, and stirred 3 h. A saturated solution of NH4Cl was added to the mixture, and the mixture was extracted thrice with EtOAc. The combined organic phase was washed with brine. The organic phase was dried over MgSO4, and the solvent was removed under reduced pressure. The flask was charged with 3,4-diethylhexane-3,4-diol, Epin (1.0 equiv) in CH2Cl2 (10 mL, 0.10 M), and stirred at room temperature. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (a mixture of hexane and EtOAc) to afford aryl boronic acid 3,4-diethylhexane-3,4-diol ester, ArB(Epin) 2.

An oven-dried Schlenk flask was charged with PdCl2(dppp)·CH2Cl2 (2.9 mg, 5.0 mol%), KOAc (29 mg, 0.30 mmol), B2(Epin)2 [1] (55 mg, 0.15 mmol) and a magnetic stirrer bar. The flask was equipped with a rubber septum and evacuated and back-filled with argon (this process was repeated three times). After 1-(4-bromophenyl)ethan-1-one (3g) (20 mg, 0.10 mmol) in anhydrous DMSO S-14 (1.0 mL, 0.10 M) was added via a syringe, the septum was replaced with a Teflon screw cap under a flow of argon, and the cap was tightly closed. The mixture was stirred for 2 h at 80 °C. After cooling to room temperature, the mixture was filtrated through a short pad of celite. The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/EtOAc = 95:5) to afford the titled compound 2s as a colorless oil (30 mg, 99%).

参考资料

一、 Aryl Boronic Esters Are Stable on Silica Gel and Reactive under Suzuki–Miyaura Coupling Conditions; Org. Lett. 2022, 24, 19, 3510–3514.

二、 Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone? J. Med. Chem. 2016, 59, 4443−4458.


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