Miyaura反应制备硼酸酯失败,试试这个方法

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Miyaura硼酸酯化反应 可以在钯催化下由芳基卤代物制备芳基硼酸酯。但是很多情况下,偶联反应无法得到相应的硼酸酯,或者产率很低,如底物中含有巯基(可能是硫可以使催化剂中毒)。这种情况下,通常我们会通过【 金属有机试剂制备单取代芳基硼酸 】,此方法通常是利用 格氏试剂或锂试剂和硼酸三甲酯在低温下反应,接着酸性条件下水解得到芳基硼酸。

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除了硼酸三甲酯和硼酸三异丙酯,还有一种比较常用的制备芳基硼酸酯的试剂,异丙醇频哪醇硼酸酯。

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利用此试剂可以直接得到芳基硼酸频哪醇酯,操作也比硼酸三甲酯更方便。实际操作中如果先拔卤制备芳基锂,再加硼酸酯反应效果不好,可以考虑先将两个底物溶于无水THF,降温至-78℃,然后缓慢滴加正丁基锂,加毕,升至室温,搅拌1小时,即可得到产物。饱和氯化铵淬灭反应,萃取,干燥,浓缩得到粗产物。如果反应干净的话,可以直接用于下一步反应,剩余的 异丙醇频哪醇硼酸酯不影响下一步 Suzuki–Miyaura反应 。

操作要点:反应要求严格无水,具体操作参考“有机合成”公众号往期文章【 Schlenk技术及无水无氧操作中物料的转移 】,溶剂可以直接购买超干溶剂,或者自己制备无水溶剂。

反应实例

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Synthesis of 2-(2,6-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaboroaneTo a solution of 1 ,3-difluoro-5-methylbenzene (1.Oeq) in dry THF(0.2M) under an atmosphere of N2 at -78°C was added n-butyllithium (leq, 1.6M in hexanes) slowly keeping the internal temperature below -65°C. The reaction was stirred for 2 hrs at -78°C, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (1.15eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHC03 (sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2S04, filtered and concentrated to yield 2-(2,6-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaboroane as a white solid in 92%. 1H NMR (400 MHz, ) δ ppm 6.67 (dd, J=9.39, 0.78 Hz, 2 H), 2.34 (s, 3 H), 1.38 (s, 12 H).

【WO2012/4217, 2012, A1】

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2-(4-Methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5): n-BuLi (2M in hexane, 21.4 mL, 3.39 g, 53.0 mmol) was added within 25 min at ‒78 °C to a solution of 4-bromoanisole (4, 3.30 mL, 4.95 g, 26.5 mmol) in anhydrous THF (120 mL). The mixture was stirred at ‒78 °C for 1.5 h, 2-isopropoxy-4,4,5,5-tetramethyl1,3,2-dioxaborolane (11.0 mL, 10.0 g, 53.8 mmol) was added and the temperature was raised to rt overnight. The mixture was brought to pH ~7 by addition of 1N HCl. EtOAc (100 mL) and brine were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated at reduced pressure to yield the product as a colorless oil (5.96 g, 25.5 mmol, 95%). The NMR-spectroscopic data were in agreement with published data: 3 1 H NMR (300 MHz, CDCl3): δ=1.33 (s, 12H, 4×CCH3), 3.82 (s, 3H, OMe), 6.90 (m, 2H, 3ʼ-H, 5ʼ-H), 7.76 ppm (m, 2H, 2ʼ-H, 4ʼ-H).

【 European Journal of Organic Chemistry , 2019, 6697 - 6701】


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