芳基甲基酮是一种非常有用的有机合成中间体，传统方法是通过直接引入乙酰基，但是此方法必须是富电子体系的芳环才能顺利进行。另外一种就是利用芳基甲酸的衍生物（如）和有机金属试剂反应制备芳基甲基酮，但此方法官能团耐受度较低。
如果利用芳基卤代物制备芳基甲基酮，可以先插羰得到芳基甲酸衍生物，再和有机金属试剂反应。后来也发展过渡金属催化的偶联反应。如，但此方法以CO为底物，操作复杂，而且CO和有机锡试剂都有毒。
另外就是直接利用，芳基溴和 三丁基(1-乙氧基乙烯)锡 反应 得到(1-乙氧基乙烯基)芳基化合物，然后水解得到芳基甲基酮。
或者利用酰氯和芳基锡试剂进行得到芳基甲基酮，但是上述方法都用到有毒的有机锡试剂 ，限制了其应用范围。
【 J. Org. Chem., 2005, 70, 8601-8604.】
另外一种就是利用，芳基卤代物和乙烯基正丁醚反应得到(1-正丁氧基乙烯基)芳基化合物，也是要水解得到芳基甲基酮。但是，活性不是很高，很多底物并不能得到较高的产率。
近期加利福尼亚大学洛杉矶分校的Neil K. Garg教授课题组报道了一个利用乙酰基三甲基硅烷和芳基溴代物在钯催化下偶联，一步得到芳基甲基酮的方法【 Org. Synth. , 2021 , 98, 68-83】。此反应条件温和，底物环境友好，毒性低，官能团耐受度高，给电子取代的芳环和吸电子取代的芳环都可以顺利反应。杂芳基溴代物也可以反应。
6-Acetylbenzothiophene (1). A single-necked (24/40 joint) 250 mL roundbottomed flask is equipped with a Teflon-coated magnetic stir bar (4.0 x 1.5 cm, football-shaped). The apparatus is flame-dried under vacuum, then cooled to 23 ºC under an atmosphere of argon (Note 2). The flask is charged sequentially with 6-bromobenzothiophene (8.00 g, 37.5 mmol, 1 equiv) (Note 3), cesium fluoride (22.8 g, 150 mmol, 4 equiv) (Note 4), and tetrakis(triphenylphosphine)palladium(0) (2.17 g, 1.88 mmol, 0.05 equiv) (Note 4) through the neck of the flask in singular portions. The neck of the flask is then fit with a rubber septum. An argon inlet needle and a purge needle are placed in the rubber septum, and the flask is purged for 5 min (Figure 1A). After 5 min, the vent needle is removed, and acetyltrimethylsilane (10.8 mL, 75 mmol, 2 equiv) (Note 5) is added in one portion over 1 min via a plastic syringe fit with an 18 G x 1.5’’ needle. 1,2-Dichloroethane (38 mL, 1 M) (Note 6) is then added to the flask via a plastic syringe fit with an 18 G x 6’’ needle in a single portion over 1 min (Figure 1B). The rubber septum is quickly removed and replaced with a separately flame-dried air condenser with a 24/40 joint (Note 7). The reaction apparatus is then placed in an oil bath preheated to 75 ºC. The reaction mixture is stirred vigorously (800 RPM) for 24 h under positive argon pressure (Figure 1C).
After 24 h (Note 8), the reaction flask is removed from the oil bath and
allowed to cool to 23 ºC (Figure 1D). Once the reaction mixture is cooled to 23 ºC, the reflux condenser is removed, and the heterogeneous mixture is diluted with heptane (75 mL) (Note 9). The solution is then filtered through a plug of silica gel (50 g, pre-wetted with 100 mL ethyl acetate) (Note 10) in a fritted Büchner funnel (Note 11) into a 1000 mL round-bottomed flask using ethyl acetate as eluent (500 mL) (Notes 12 and 13). The filtrate is then concentrated under reduced pressure (31 °C, from 100 mmHg to 50 mmHg).
The resultant brown solid is purified via column chromatography using
an OD 7.5 x 12 cm column of 250 g silica gel (Note 14) and eluted sequentially with 1400 mL 14:1 heptane:EtOAc and 2000 mL 9:1 heptane:EtOAc. The eluate is collected using 25 mL test tubes to provide the product in fractions 78–106 (Note 15). The fractions are combined in a collection flask and concentrated by rotary evaporation under reduced pressure (31 ºC, 90 mmHg). The material is then transferred to an 8-dram vial and dried under high vacuum for 30 min (<1 mmHg) to afford 6-acetylbenzothiophene (1) asa yellow powder (4.15 g, 63% yield) (Notes 16, 17 and 18).
参考资料
Org. Synth.2021, 98, 68-83；DOI: 10.15227/orgsyn.098.0068
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