官能团转化新大招：酯基一步直接还原为醚

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？

本期小编就给大家介绍一种由酯基直接一步制备醚的简单方法。BH3-NH3是硼烷−四氢呋喃（BTHF）和硼烷−二甲基硫醚（BMS）的一种类似物，它对空气和湿气都比较稳定，便于操作。

底物范围（烷基酯）：含甲氧基和硝基的酯2c和2d分别以99%和96%的产率得到醚4c和4d。值得注意的是，甲氧基对TiCl4−BH3-NH3体系具有耐受性。酯基的α位也可以有不同的取代基，包括甲基（2e）、苯基（2f）和溴（2g），都能以86−97%的分离产率得到相应的醚（4e−4g）。3-苯基丙酸乙酯（2j）以定量（99%）产率得到4j。乙酸苄酯（2k）与苄氧基部分的反应以69%的产率提供苄基乙醚（4k）。对称和不对称直链烷基酯2l−2n成功地转化为醚4l−4n，产率为87−99%。由2°-和3°-烷基酸衍生的酯，环己烷羧酸乙酯（2o）和金刚烷-1-羧酸乙酯（2p），都以不错的产率得到醚。远端双键和三键也能完整保留，不饱和醚4q和4r以接近定量的产率（98−99%）获得。但是，（Z）-油酸甲酯（2s）的内部双键被氢化得到了4s，产率为95%。

对于芳基酯该条件也是可以顺利发生脱氧的：丁基、5-氯正戊基和苯甲酸异丙酯（2u−2w）均脱氧为相应的醚（4u−4w），产率为75−99%。可以兼容给电子或吸电子基团的取代，并且以82−84%的产率获得相应的醚4x−4ac。芳香二酯邻苯二甲酸二乙酯（2ad）以47%的产率转化为所需的二酯（4ad）。类似地，环状酯邻苯二甲酸酯（2ae）以48%的产率转化为环状醚4ae。含有杂原子的4af和4ag分别以97%和43%的产率得到。在当前的反应条件下，含有腈或酰胺官能团的底物是不相容的。

使用BF3-Et2O作为lewis acid时，反应可以直接将酯基还原得到醇。具体条件细节差异可看下方实验操作步骤。

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。