CN114957170B - 一种醚类化合物邻位碳-氢键直接单氟烯基化反应 - Google Patents
一种醚类化合物邻位碳-氢键直接单氟烯基化反应 Download PDFInfo
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Abstract
本发明属于有机合成领域，公开了一种醚类化合物的邻位碳‑氢键直接单氟烯烃化反应，用于制备含有醚的的单氟烯烃的反应。以氟代丙烯酸和醚类化合物为原料，以溴化亚铜为催化剂、二叔丁基过氧化物(DTBP)为引发剂进行反应，得到具有Z‑构型单氟烯烃化合物。采用本发明方法制备单氟烯烃避免使用昂贵的铱催化剂。反应原料易得、原料来源广、产物收率和选择性高，本反应体系加料方式简单，合成经济价值高。为醚类化合物邻位碳‑氢键直接单氟烯基化反应提供了高效、便捷、经济的制备方法。
Description
技术领域
本发明涉及化合物制备，属于有机合成领域。具体涉及醚类化合物的邻位碳-氢键直接单氟烯烃化反应，用于制备含有醚的的单氟烯烃。
背景技术
有机分子中引入氟原子可以增加母体分子的亲酯性、水溶性和代谢稳定性。因此，含氟结构片段的引入在药物研究和功能材料发展上有着重要的价值。目前大约25％的医药分子和40％的农药分子中至少都含有一个氟原子。其中，单氟烯烃由于可以作为一类重要的有机含氟合成子，在有机合成上有着重要的应用。此外，单氟烯烃还可以作为酰胺键的电子等排体，增加分子的构象稳定性和肽酶的水解稳定性，在药物研究中有着重要的价值。因此很多活性分子中都含有单氟烯烃片段(式1)。
碳-氢键的直接单氟烯基化是一种直接、高效、和经济的合成单氟烯烃化合物的方法。然而现有的碳-氢键的直接单氟烯基化大多数都是sp2碳-氢键的单氟烯基化为主。sp3碳-氢键的单氟烯基化反应是很少的。2016年，Hashmi等人报道了光催化谐二氟烯烃与三级胺的单氟烯基化反应。然而该反应需要使用预先制备的昂贵的金属铱[二[2-(2，4-二氟苯 基)-5-三氟甲基吡啶][2-2′-联吡啶]铱二(六氟磷酸)盐，大约2000元/克]为催化剂，并且对于合成三取代的单氟烯烃，该反应只有2∶1到3∶1的Z/E选择性。这就给产物的分离带来的一定的困难(式2，Angew.Chem.，Int.Ed.，2016，55，9416-9421)。
接着Wang等人报道了光催化谐二氟烯烃与醚类化合物的单氟烯基化反应。同样的该反应也需要使用昂贵的金属铱[二[2-(2，4-二氟苯基)-5-三氟甲基吡啶][2-2′-联吡啶] 铱二(六氟磷酸)盐]为催化剂，并且对于合成三取代的单氟烯烃，该反应只有1∶1到2∶1的Z/E选择性，产物分类困难(式3，Org.Lett.，2019，21，4585-4589)。
最近Deng等人也报道了光催化谐二氟烯烃与碳-氢的单氟烯基化反应，然而该反应也需要使用昂贵的金属铱[二[2-(2，4-二氟苯基)-5-三氟甲基吡啶][2-2′-联吡啶]铱二 (六氟磷酸)盐]为催化剂，并且对于合成三取代的单氟烯烃，该反应只有1∶1到3∶1的Z/E选择性(式4，Org.Chem.Front.，2022，9，959-965)。
单氟烯烃是一类重要的有机含氟合成子，并且单氟烯烃可以作为酰胺键的电子等排体。因此高效、廉价的通过C-H键直接单氟烯基化构建单氟烯烃在有机合成和药物研究领域有着重要的价值。
发明内容
针对目前醚类邻位碳-氢键直接单氟烯基化合成重要的单氟代烯基反应存在的缺点：需要使用昂对的金属铱催化剂，且对于合成三取代单氟烯烃产物的Z/E选择性大约只有1∶1到3∶1。本发明提供了使用廉价的溴化亚铜(大约0.25元/克)为催化剂，高效的实现了醚类化合物邻位碳-氢键的单氟烯基化反应，且该反应有着卓越的Z/E选择性(Z∶E＞20∶1)。
为解决上述技术问题，本发明采用如下技术方案：一种醚类化合物邻位碳-氢键直接单氟烯基化反应，其特征在于：以氟代丙烯酸和醚类化合物为原料，以溴化亚铜为催化剂、二叔丁基过氧化物(DTBP)为引发剂，按下述反应式进行反应，得到具有通式(I)的Z-单氟烯烃化合物：
其中R为芳基或者烯基取代基；
优选地，所述溴化亚铜的物质的量为氟代丙烯酸的物质的量的10％。
优选地，所述DTBP的物质的量为氟代丙烯酸的物质的量的3倍。
优选地，反应温度为100℃，反应时间为18h。
该方法第一次实现了以廉价的溴化亚铜为催化剂高效、高选择性的实现了醚类化合物邻位碳-氢键的直接单氟烯基化反应。采用本发明方法制备单氟烯烃避免使用昂贵的铱催化剂。反应原料易得、原料来源广、产物收率和选择性高，本反应体系加料方式简单，合成经济价值高。为醚类化合物邻位碳-氢键直接单氟烯基化反应提供了高效、便捷、经济的制备方法。
具体实施方式
下面通过具体实施方式对本发明的技术方案进行做进一步说明：
实施例1，该实施例的反应式如下所示：
(1)在空气下，溴化亚铜(10mol％)和α-氟代肉桂酸(0.2mmol)加入到一个带支管、含有磁子的密封反应管中，反应管抽冲氩气三次。在氩气保护下，向反应管中加入1.5mL四氢呋喃和二叔丁基过氧化物(3equiv)，塞紧活塞，置于110℃油浴锅中搅拌反应18小时。
(2)将步骤(1)中所得物料加入乙酸乙酯充分混合，用短硅胶柱过滤掉固体残渣后，保留有机相。
(3)旋干步骤(2)中所得的有机相中的溶剂，得到粗产物，然后用硅胶柱纯化粗产物。洗脱剂为石油醚和乙酸乙酯混合物，分离收率为78％，Z/E＞30∶1，产物纯度100％。
实施例2
该实施例的反应式如下所示：
(1)在空气下，溴化亚铜(10mol％)和4-氟-α-氟代肉桂酸(0.2mmol)加入到一个带支管、含有磁子的密封反应管中，反应管抽冲氩气三次。在氩气保护下，向反应管中加入1.5mL四氢呋喃和二叔丁基过氧化物(3equiv)，塞紧活塞，置于110℃油浴锅中搅拌反应18小时。
(2)将步骤(1)中所得物料加入乙酸乙酯充分混合，用短硅胶柱过滤掉固体残渣后，保留有机相。
(3)旋干步骤(2)中所得的有机相中的溶剂，得到粗产物，然后用硅胶柱纯化粗产物。洗脱剂为石油醚和乙酸乙酯混合物，分离收率为76％，Z/E＞30∶1，产物纯度100％。
实施例3
该实施例的反应式如下所示：
(1)在空气下，溴化亚铜(10mol％)和4-氯-α-氟代肉桂酸(0.2mmol)加入到一个带支管、含有磁子的密封反应管中，反应管抽冲氩气三次。在氩气保护下，向反应管中加入1.5mL四氢呋喃和二叔丁基过氧化物(3equiv)，塞紧活塞，置于110℃油浴锅中搅拌反应18小时。
(2)将步骤(1)中所得物料加入乙酸乙酯充分混合，用短硅胶柱过滤掉固体残渣后，保留有机相。
(3)旋干步骤(2)中所得的有机相中的溶剂，得到粗产物，然后用硅胶柱纯化粗产物。洗脱剂为石油醚和乙酸乙酯混合物，分离收率为71％，Z/E＞30∶1，产物纯度100％。
实施例4
该实施例的反应式如下所示：
(1)在空气下，溴化亚铜(10mol％)和3-溴-α-氟代肉桂酸(0.2mmol)加入到一个带支管、含有磁子的密封反应管中，反应管抽冲氩气三次。在氩气保护下，向反应管中加入1.5mL 1，4-二氧六环和二叔丁基过氧化物(3equiv)，塞紧活塞，置于110℃油浴锅中搅拌反应18小时。
(2)将步骤(1)中所得物料加入乙酸乙酯充分混合，用短硅胶柱过滤掉固体残渣后，保留有机相。
(3)旋干步骤(2)中所得的有机相中的溶剂，得到粗产物，然后用硅胶柱纯化粗产物。洗脱剂为石油醚和乙酸乙酯混合物，分离收率为67％，Z/E＞30∶1，产物纯度100％。
实施例5
该实施例的反应式如下所示：
(1)在空气下，溴化亚铜(10mol％)和β-氟代肉桂酸(0.2mmol)加入到一个带支管、含有磁子的密封反应管中，反应管抽冲氩气三次。在氩气保护下，向反应管中加入1.5mL 1，4-二氧六环和二叔丁基过氧化物(3equiv)，塞紧活塞，置于110℃油浴锅中搅拌反应18小时。
(2)将步骤(1)中所得物料加入乙酸乙酯充分混合，用短硅胶柱过滤掉固体残渣后，保留有机相。
(3)旋干步骤(2)中所得的有机相中的溶剂，得到粗产物，然后用硅胶柱纯化粗产物。洗脱剂为石油醚和乙酸乙酯混合物，分离收率为63％，Z/E＞30∶1，产物纯度100％。
所用的各物质的量及反应条件同实施例进行实验拓展，以说明本发明的技术方案具有良好的官能团兼容性。
以上已将本发明做一详细说明，以上所述，仅为本发明之较佳实施例而已，当不能限定本申请实施范围，即凡依本申请范围所作均等变化与修饰，皆应仍属本发明涵盖范围。
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图1为本发明制备的产物1的核磁共振氢谱；
图2为本发明制备的产物1的核磁共振碳谱；
图3为本发明制备的产物1的核磁共振氟谱；
图4为本发明制备的产物2的核磁共振氢谱；
图5为本发明制备的产物2的核磁共振碳谱；
图6为本发明制备的产物2的核磁共振氟谱；
图7为本发明制备的产物3的核磁共振氢谱；
图8为本发明制备的产物3的核磁共振碳谱；
图9为本发明制备的产物3的核磁共振氟谱；
图10为本发明制备的产物4的核磁共振氢谱；
图11为本发明制备的产物4的核磁共振碳谱；
图12为本发明制备的产物4的核磁共振氟谱；
图13为本发明制备的产物5的核磁共振氢谱；
图14为本发明制备的产物5的核磁共振碳谱；
图15为本发明制备的产物5的核磁共振氟谱；
图16为本发明制备的产物6的核磁共振氢谱；
图17为本发明制备的产物6的核磁共振碳谱；
图18为本发明制备的产物6的核磁共振氟谱；
图19为本发明制备的产物7的核磁共振氢谱；
图20为本发明制备的产物7的核磁共振碳谱；
图21为本发明制备的产物7的核磁共振氟谱；
图22为本发明制备的产物8的核磁共振氢谱；
图23为本发明制备的产物8的核磁共振碳谱；
图24为本发明制备的产物8的核磁共振氟谱；
图25为本发明制备的产物9的核磁共振氢谱；
图26为本发明制备的产物9的核磁共振碳谱；
图27为本发明制备的产物9的核磁共振氟谱；
图28为本发明制备的产物10的核磁共振氢谱；
图29为本发明制备的产物10的核磁共振碳谱；
图30为本发明制备的产物10的核磁共振氟谱；
图31为本发明制备的产物11的核磁共振氢谱；
图32为本发明制备的产物11的核磁共振碳谱；
图33为本发明制备的产物11的核磁共振氟谱；
图34为本发明制备的产物12的核磁共振氢谱；
图35为本发明制备的产物12的核磁共振碳谱；
图36为本发明制备的产物12的核磁共振氟谱；
图37为本发明制备的产物25的核磁共振氢谱；
图38为本发明制备的产物25的核磁共振碳谱；
图39为本发明制备的产物25的核磁共振氟谱；
图40为本发明制备的产物26的核磁共振氢谱；
图41为本发明制备的产物26的核磁共振碳谱；
图42为本发明制备的产物26的核磁共振氟谱；
图43为本发明制备的产物27的核磁共振氢谱；
图44为本发明制备的产物27的核磁共振碳谱；
图45为本发明制备的产物27的核磁共振氟谱；
图46为本发明制备的产物28的核磁共振氢谱；
图47为本发明制备的产物28的核磁共振碳谱；
图48为本发明制备的产物28的核磁共振氟谱。
Claims (1)
1.一种通过醚类化合物邻位碳-氢键直接单氟烯基化反应制备Z-单氟烯烃化合物的方法，其特征在于：以氟代丙烯酸和醚类化合物为原料，以溴化亚铜为催化剂、二叔丁基过氧化物为引发剂，按下述反应式进行反应，得到Z-单氟烯烃化合物，
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