仲胺在伯胺存在下选择性进行烷基化和酰基化，可以放大哦
文摘
科学
2024-10-17 09:00
四川
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点击上方蓝色文字进行关注首先小编提出一个问题，如何简便的进行如下反应？简单一步可以实现吗？知道的童鞋可以私信小编，讨论一二。
看了本期小编将要介绍的方法，相信你会有举一反三的想法。该方法是通过使用反应溶剂甲基异丁基酮（MIBK）作为伯胺的临时保护基来进行的。仲胺酰化或烷基化后，所得亚胺中间体可以被顺利水解，得到高产率和高纯度的游离伯胺。该方法代表了一种廉价且可放大的替代方案，可替代需要多种保护和脱保护的多步骤方法。研究者发现在1-氯-3-甲氧基丙烷存在下，用碳酸钠在MIBK中加热1选择性地产生烷基化亚胺2。2的水解以良好的产率和高纯度提供了游离伯胺3。相反，在其他溶剂中进行的1的烷基化反应得到3，则具有大量的多烷基化产物。针对不同沸点的胺，作者提供了三个不同的实验方法：高沸点的游离二胺可以通过共沸蒸馏脱水定量转化为亚胺（表1，方法A）。低沸点游离二胺则通过在脱水剂如硫酸镁或硫酸钠存在下加热将其转化为希夫碱（表1，方法B）。最后，盐酸盐铵盐需要碳酸钠来释放游离碱，并共沸蒸馏允许去除水（表1，方法C）。从下表可以看出，仲胺的Boc保护选择性都非常优秀，都在90/10以上。与卤代烷基的反应情况下，则需要一种额外当量的无机碱来捕获释放的酸。苄基化得到高产率的含有8%二苄基化产物的一苄基化产物。然而，在亚胺水解之前，我们观察到与苄基氯的反应产生的二苄基化产物少于0.5%。这可以通过亚胺和胺在GC中的响应因子的差异来解释。与烯丙基溴反应获得的低产率可能是由于后处理过程中产物的损失。For Boc：A mixture of 4-(aminomethyl)-piperidine (57 g, 0.5 mol) and anhydrous MgSO4 (30 g, 0.25 mol) in MIBK (1000 mL, 2 L/M) was heated to reflux under nitrogen. After no more starting material was observed by GC, the reaction mixture was cooled to 0 °C. To this mixture, was added dropwise to a solution of BOC anhydride (109 g, 0.5 mol) dissolved in a minimum of MIBK. After stirring for 0.5 h at room temperature, water (100 mL, 0.2 L/M) was added to dissolve inorganic salts. The aqueous layer was split off, and MIBK was evaporated under reduced pressure leading to the imine intermediate. Water (50 mL) and 2-propanol (500 mL) were then added, and the mixture was heated to 50 °C until completion of the hydrolysis. Solvents were then distilled off providing tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (98.4 g, 92% yield).For alkylation: MIBK (2 L/M) was added to a flask containing the diamine hydrochloride salt (1 equiv) and sodium carbonate (3.5 equiv). The heterogeneous mixture was heated to reflux under nitrogen, and water was removed from the reaction mixture with a Dean-Stark trap. When the imine formation went to completion, the flask was cooled to room temperature. Alkyl halide (1 equiv) was then added to the mixture. After the mixture stirred overnight at room temperature, water (0.5 L/M) was added. The aqueous layer was split off, and MIBK was evaporated under reduced pressure leading to the imine intermediate. Water and 2-propanol were then added, and the mixture was heated to 50 °C until completion of the hydrolysis. Solvents were then distilled off providing the free primary amine. 点了在看![]()
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