醚是天然分子和合成分子不可分割的一部分,其中许多具有重要的药用特性。醚合成的经典方法包括由醇或酚进行的Williamson 和Ullmann反应。考虑到酯在自然界中的可用性,或在制药和精细化学工业中可通过羧酸和醇缩合容易制备的特点,所以直接通过酯脱氧制备醚是一个极好的过程。然而,优先于羧酸盐去除羰基氧是具有挑战性的。
在我们基础有机合成化学的官能团转化知识体系中,由酯基合成醚往往需要预先将酯基还原为醇,再与烷基卤代物取代而制得,其中烷基卤代物可能不容易获得,亲核取代的官能团兼容性也可能存在问题,所以这并不是一个很好的转化方法。那么是否可以酯基将酯基转化成醚呢?
实验操作如下:
A 50 mL oven dried round bottom flask was charged with ester (1 mmol, 1 equiv.) and a magnetic stirring bar. The flask was sealed using a rubber septum. After purging the flask with nitrogen, dry diethyl ether (or other solvents) (3 mL) was added, and the solution was cooled at 0 °C with an ice bath. Subsequently, TiCl4 (or other Lewis acids) (2.0 mmol, 2.0 equiv.) was added to the mixture, dropwise via syringe if a liquid or by temporarily removing the septum (under a flow of nitrogen) if a solid. The septum was then carefully opened (under a flow of nitrogen) and borane-ammonia (or other solid borane-amine) (2.5 mmol, 2.5 equiv.) was added slowly to the reaction mixture. Upon complete addition the reaction flask was again sealed with a septum. After stirring at 0 °C for 1 min, the reaction mixture was allowed to warm up to room temperature, stirred and monitored by TLC until completion. On completion of the reaction, the crude mixture was brought to 0 °C and quenched by slow addition of cold 1 M HCl, then transferred to a separatory funnel and extracted with diethyl ether (2 × 3 mL). The combined organic layers were washed with brine (1x 3 mL), dried over anhydrous sodium sulfate, filtered through cotton, and concentrated under aspirator vacuum using a rotary evaporator. Any remaining traces of solvent were removed by subjecting to high vacuum for 30 min. Column chromatography was performed only if necessary to further purify the product using a hexane: ethyl acetate (v/v = 90:10) solvent system to afford the desired product.
A 50 mL oven dried round bottom flask was charged with ester (1 mmol, 1 equiv.) and a magnetic stirring bar. The flask was sealed using a rubber septum. After purging the flask with nitrogen, dry diethyl ether (3 mL) was added, and the solution was cooled at 0 °C with an ice bath. Subsequently, BF3-OEt2 (1.5 mmol, 1.5 equiv.) was added to the mixture, dropwise via syringe. The septum was then carefully opened (under a flow of nitrogen) and ammonia borane (2.5 mmol, 2.5 equiv.) was added slowly to the reaction mixture. Upon complete addition the reaction flask was again sealed with a septum. After stirring at 0 °C for 1 minute, the reaction mixture was allowed to warm up to room temperature, stirred and monitored by TLC until completion. On completion of the reaction, the crude mixture was brought to 0 °C and quenched by slow addition of cold 1 M HCl, then transferred to a separatory funnel and extracted with diethyl ether (2 × 3 mL). The combined organic layers were washed with brine (1 x 3 mL), dried over anhydrous sodium sulfate, filtered through cotton, and concentrated under aspirator vacuum using a rotary evaporator. Any remaining traces of solvent were removed by subjecting to high vacuum for 30 min. Column chromatography was performed only if necessary to further purify the product using a hexane: ethyl acetate (v/v = 90:10) solvent system to afford the desired product。
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