官能团转化新大招：酯基一步直接还原为醚！
文摘
科学
2024-12-11 07:35
四川
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点击上方蓝色文字进行关注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？
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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。![]()
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。 点了在看![]()
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