通过铃木交叉偶联和烯烃硼羧化反应合成硼化布洛芬衍生物
Summary
本协议描述了一种详细的台式催化方法，该方法产生布洛芬的独特硼化衍生物。
Abstract
非甾体抗炎药（NSAIDs）是用于管理和治疗疼痛和炎症的最常见药物之一。2016年，在温和条件下，通过使用二氧化碳（CO2球囊）和二硼还原剂对乙烯基芳烃进行铜催化的区域选择性硼酸羧基化反应，合成了一类新的硼官能化非甾体抗炎药（bora-NSAIDs）。这种原始方法主要在手套箱或真空气体歧管（舒伦克线）中在严格的无空气和无湿气条件下进行，这通常由于痕量杂质而导致反应结果不可重现。本协议描述了一种更简单、更方便的台式方法，用于合成具有代表性的硼烷酮-NSAID，硼酸-布洛芬。1-溴-4-iso丁基苯和乙烯基硼酸频哪醇酯之间的铃木-宫浦交叉偶联反应生成4-异丁基苯乙烯。苯乙烯随后被区域选择性地硼胺羧化，以提供硼酸-布洛芬，一种α-芳基-β-硼基丙酸，在多克范围内具有良好的产率。该程序允许在合成实验室中更广泛地利用铜催化的硼羧化，从而能够进一步研究硼-非甾体抗炎药和其他独特的硼功能化药物样分子。
Introduction
有机硼化合物在化学合成中已被战略性地用于50多年1，2，3，4，5，6。氢硼化-氧化7，8，9，10，卤化11，12，胺化13，14和铃木-宫浦交叉偶联15，16，17等反应导致了化学和相关学科的重大多学科创新。例如，铃木-宫浦反应占所有碳-碳键形成反应的40%，以追求候选药物18。铃木-宫浦交叉偶联反应从卤代芳烃前驱体19一步产生乙烯基芳烃。相对于传统的Wittig合成，这种更环保的催化策略具有价值，这些醛的原子经济性差，并产生化学计量的三苯基氧化膦副产物。
据预测，乙烯基芳烃的区域选择性异（元素）羧化将允许直接获得新型含异（元素）的非甾体抗炎药（NSAIDs），直接利用CO2进行合成。然而，杂（元素）羧化反应极为罕见，并且在2016年之前仅限于炔基和丙烯基底物20，21，22。硼羧化反应扩展到乙烯基芳烃将提供硼官能化的NSAIDs，并且基于硼的候选药物（图1）越来越受欢迎，正如FDA最近批准化疗性硼替佐米，抗真菌他伐硼罗和抗炎克立硼罗的决定所表明的那样。从药物设计的角度来看，硼的路易斯酸度很有趣，因为它能够容易地结合路易斯碱基，例如二醇、碳水化合物上的羟基或 RNA 和 DNA 中的氮碱基，因为这些路易斯碱基在生理和病理过程中起着重要作用23。
这种硼羧化的催化方法依赖于铜硼酰中间体对烯烃的硼基化，然后将CO2 插入到所得的Cu-烷基中间体中。Laitar等报道了通过使用（NHC）Cu-硼基24对苯乙烯衍生物进行硼基化，并且Cu-烷基物种的羧化反应也得到了证实25。2016年，Popp实验室开发了一种新的合成方法，使用（NHC）Cu-硼基催化剂和仅1个大气压的气态CO226实现乙烯基芳烃的轻度二官能化。使用该方法，只需一步即可获得α-芳基丙酸药效团，并且可以制备出一类新型未开发的硼修饰非甾体抗炎药，并具有优异的产率。2019年，催化添加剂提高了催化剂效率并拓宽了底物范围，包括制备另外两种新型硼化NSAIDs27 （图1）。
以前的烯烃硼羧化反应只能在严格的无空气和无湿气条件下使用分离的N-杂环卡宾连接铜（I）预催化剂（NHC-Cu;NHC = 1，3-双（环己基）-1，3-二氢-2H-咪唑-2-亚基，ICy）。对于合成界来说，可以使用简单的试剂合成硼化布洛芬的台式方法将更理想，这促使我们开发允许乙烯基芳烃（特别是4-异丁基苯乙烯）硼酸羧基化的反应条件，从原 位 生成NHC-Cu预催化剂开始，而无需手套箱。最近，据报道使用咪唑盐和氯化铜（I）原 位 生成活性NHC连接的铜（I）催化剂28的硼羧化方案。使用这种方法，α-甲基苯乙烯被硼烷基化，以获得所需产物的71%分离产率，尽管使用了手套箱。受这一结果的启发，设计了一种在不使用氮填充手套箱的情况下对硼羧酸叔丁基苯乙烯进行改进的程序。以1.5 g规模生产所需的硼羧化叔丁基苯乙烯产品，收率为90%。令人欣慰的是，该方法可以应用于4-异丁基苯乙烯，以生产中等收率的 硼-布洛芬NSAID衍生物。α-芳基丙酸药效团是非甾体抗炎药的核心基序;因此，允许直接访问该基序的合成策略是非常理想的化学转化。本文介绍了一种合成途径，该途径可以从丰富、廉价的 1-溴-4-异丁基苯起始材料（~2.50 美元/1 g）中获取独特的 硼-布洛芬 NSAID 衍生物，分两步获得中等产量，无需手套箱。
Protocol
Representative Results
Discussion
4-异丁基苯乙烯（1）是通过铃木交叉偶联反应从廉价的市售1-溴-4-异丁基苯和乙烯基硼酸频哪醇酯中有效获得的。与Wittig方法相比，该反应允许以更环保的方式和更好的原子经济性生产所需的苯乙烯。通过TLC进行反应监测对于确保1-溴-4-异丁基苯底物的完全转化至关重要，因为反应未进行完全转化会导致底物和产物的快速色谱分离困难。
4-异丁基苯乙…
Divulgazioni
The authors have nothing to disclose.
Acknowledgements
我们要感谢美国国家科学基金会CAREER和MRI计划（CHE-1752986和CHE-1228336），西弗吉尼亚大学荣誉EXCEL论文计划（ASS和ACR），西弗吉尼亚大学研究学徒（RAP）和暑期本科生研究体验（SURE）计划（ACR），以及Brodie家族（Don和Linda Brodie创新资源基金）对这项研究的慷慨支持。
Materials
| 125 mL filtration flask | ChemGlass | ||
| 20 mL vial with pressure relief cap | ChemGlass | ||
| 4-isobutylbromobenzene | Matrix scientific | 8824 | |
| Anhydrous potassium carbonate | Beantown chemicals | 124060 | |
| Anhydrous sodium sulfate | Oakwood | 44702 | |
| Bis(pinacolato)diboron | Boron Molecular chemicals | BM002 | |
| Buchner funnel with rubber adaptor | ChemGlass | ||
| Carbon dioxide gas (Bone dry) | Mateson | Tygon tubing connects cylinder regulator to needle used for reaction purging | |
| COPPER(I) CHLORIDE, REAGENT GRADE, 97% | Aldrich | 212946 | |
| Dichloromthane – high purity | Fisher | D37-20 | |
| Diethyl ether – high purity | Fisher | E138-20 | |
| Erlenmyer Flask, 125 mL | ChemGlass | CG-8496-125 | |
| filter paper | Fisher | ||
| Heptane | Fisher | H360-4 | |
| Hydrochloric acid | Fisher | AC124635001 | |
| IKA stirring hot plate | Fisher | 3810001 RCT Basic MAG | |
| Nitrogen filled glove box | MBRAUN | ||
| Palladium(0) tetrakistriphenylphosine | Ark Pharm | ||
| SilicaFlash P60 silica gel | SiliCycle | R12030B | |
| Sodium bicarbonate | Fisher | S233-3 | |
| Sodium tert-butoxide | Fisher | A1994222 | |
| Tetrahydrofuran – high purity | Fisher | T425SK-4 | Dried on a GlassContours Solvent Purification System |
| Triphenylphosphine | Sigma | T84409 | |
| Vacuum/gas manifold | Used for glovebox boracarboxyaltion reaction setup | ||
| Vinylboronic acid pinacol ester | Oxchem |
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