PDF(Pubmed)
Abstract：
The Heck reaction is widely employed to build a variety of biologically relevant scaffolds and has been successfully implemented in the production of active pharmaceutical ingredients (APIs). Typically, the reaction with terminal alkenes gives high yields and stereoselectivity toward the trans-substituted alkenes product, and many green variants of the original protocol have been developed for such substrates. However, these methodologies may not be applied with the same efficiency to reactions with challenging substrates, such as internal olefins, providing trisubstituted alkenes. In the present work, we have implemented a Heck reaction protocol under green conditions to access trisubstituted alkenes as final products or key intermediates of pharmaceutical interest. A set of preliminary experiments performed on a model reaction led to selecting a simple and green setup based on a design of experiments (DoE) study. In such a way, the best experimental conditions (catalyst loading, equivalents of alkene, base and tetraalkylammonium salt, composition, and amount of solvent) have been identified. Then, a second set of experiments were performed, bringing the reaction to completion and considering additional factors. The protocol thus defined involves using EtOH as the solvent, microwave (mw) irradiation to achieve short reaction times, and the supported catalyst Pd EnCat®40, which affords an easier recovery and reuse. These conditions were tested on different aryl bromides and internal olefines to evaluate the substrate scope. Furthermore, with the aim to limit as much as possible the production of waste, a simple isomerization procedure was developed to convert the isomeric byproducts into the desired conjugated E alkene, which is also the thermodynamically favoured product. The approach herein disclosed represents a green, efficient, and easy-to-use handle towards different trisubstituted alkenes via the Heck reaction.
摘要：
Heck反应被广泛用于构建各种生物相关支架，并已成功用于生产活性药物成分（API）。通常,与末端烯烃的反应对反式取代的烯烃产物具有较高的产率和立体选择性，和原始协议的许多绿色变体已被开发用于此类底物。然而,这些方法可能无法以相同的效率应用于具有挑战性底物的反应，如内烯烃，提供三取代的烯烃。在目前的工作中,我们在绿色条件下实施了Heck反应方案，以获得三取代的烯烃作为最终产物或具有药物意义的关键中间体。对模型反应进行的一组初步实验导致基于实验设计（DoE）研究选择简单且绿色的设置。以这样的方式,最佳实验条件(催化剂负载量，烯烃的等价物，碱和四烷基铵盐，composition,和溶剂的量)已经确定。然后，进行了第二组实验，使反应完成并考虑其他因素。如此定义的方案涉及使用EtOH作为溶剂，微波（MW）辐射以实现短反应时间，和负载型催化剂PdEnCat®40，它提供了更容易的回收和再利用。在不同的芳基溴化物和内部烯烃上测试这些条件以评估底物范围。此外，为了尽可能限制废物的产生，开发了一种简单的异构化程序，将异构副产物转化为所需的共轭烯烃，这也是热力学上最受欢迎的产品。本文公开的方法代表绿色，高效,和易于使用的处理对不同的三取代的烯烃通过Heck反应。
