不用Stille偶聯，一種新的無毒的芳基溴的乙酰基化反應

芳基甲基酮是一種非常有用的有機合成中間體，傳統方法是通過直接引入乙酰基，但是此方法必須是富電子體系的芳環才能順利進行。另外一種就是利用芳基甲酸的衍生物（如）和有機金屬試劑反應制備芳基甲基酮，但此方法官能團耐受度較低。

如果利用芳基鹵代物制備芳基甲基酮，可以先插羰得到芳基甲酸衍生物，再和有機金屬試劑反應。后來也發展過渡金屬催化的偶聯反應。如，但此方法以CO為底物，操作復雜，而且CO和有機錫試劑都有毒。

另外就是直接利用，芳基溴和 三丁基(1-乙氧基乙烯)錫 反應 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錫試劑進行得到芳基甲基酮，但是上述方法都用到有毒的有機錫試劑 ，限制了其應用范圍。

【 J. Org. Chem., 2005, 70, 8601-8604.】

另外一種就是利用，芳基鹵代物和乙烯基正丁醚反應得到(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較高的產率。

近期加利福尼亞大學洛杉磯分校的Neil K. Garg教授課題組報道了一個利用乙酰基三甲基硅烷和芳基溴代物在鈀催化下偶聯，一步得到芳基甲基酮的方法【 Org. Synth. , 2021 , 98, 68-83】。此反應條件溫和，底物環境友好，毒性低，官能團耐受度高，給電子取代的芳環和吸電子取代的芳環都可以順利反應。雜芳基溴代物也可以反應。

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).

參考資料

Org. Synth.2021, 98, 68-83；DOI: 10.15227/orgsyn.098.0068