Development of a Direct Alkynylation of Carboxylic Acids

羧酸直接炔基化的发展

• 批准号: 387555981
• 负责人: Professor Dr. Manuel van Gemmeren
• 金额: --
• 依托单位: Otto Diels - Institut für Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/387555981?language=en
• 关键词: Development; Direct; Alkynylation; Carboxylic; Acids

Terminal alkynes constitute highly versatile intermediates in organic synthesis. The most established methods to prepare these compounds, such as the Seyferth-Gilbert reaction or the Corey-Fuchs protocol, require aldehydes as starting materials. This can often be disadvantageous, since these sensitive compounds have to be protected or masked in the preceding reactions, thus leading to additional synthetic steps. In many cases, the aldehyde is directly or indirectly obtained from a carboxylic acid derivative. It would therefore be desirable, if carboxylic acids could directly be converted to alkynes. However, despite the significant synthetic potential, such a methodology has remained unknown to date and therefore constitutes the objective of this project. Our strategy is based on the design of functionalized C(sp3)-nucleophiles. These reagents should be employed in a cross-coupling with the in situ activated carboxylic acid and deliver intermediates, which are predisposed towards an intramolecular cyclization. The resulting cyclic compounds should in turn be capable of undergoing a fragmentation reaction to liberate the desired alkyne alongside highly stabilized by-products, which provide the required driving force to this key step. Despite the fact that neither the proposed reagents nor the targeted overall process have been described to date, literature analogies and theoretical investigations presented in this project indicate that each individual step should in principle be feasible. Through a systematic design of the proposed reagents and a thorough optimization of the reaction conditions, a protocol is to be developed that unifies all steps from the carboxylic acid activation to the fragmentation, thus providing a valuable new tool for synthetic organic chemistry: A direct alkynylation of carboxylic acids. Particular emphasis will be placed on the broad and convenient applicability of the method, which will be studied and demonstrated in the final stages of this project.

末端炔是有机合成中用途广泛的中间体。制备这些化合物的最成熟的方法，如Seyferth-Gilbert反应或Corey-Fuchs方案，需要醛作为起始材料。这通常是不利的，因为这些敏感化合物必须在前面的反应中被保护或掩蔽，从而导致额外的合成步骤。在许多情况下，醛直接或间接从羧酸衍生物获得。因此，如果羧酸可以直接转化为炔，则将是期望的。然而，尽管有巨大的合成潜力，但迄今为止，这种方法仍然是未知的，因此构成了本项目的目标。我们的策略是基于功能化的C（sp3）-亲核试剂的设计。这些试剂应用于与原位活化的羧酸的交叉偶联，并递送倾向于分子内环化的中间体。所得到的环状化合物应该能够进行断裂反应，以释放出所需的炔以及高度稳定的副产物，这为这一关键步骤提供了所需的驱动力。尽管迄今为止尚未描述拟定试剂和目标总体工艺，但本项目中提出的文献类比和理论研究表明，原则上每个步骤都是可行的。通过对所提出试剂的系统设计和对反应条件的彻底优化，将开发一种方案，该方案将从羧酸活化到片段化的所有步骤统一起来，从而为合成有机化学提供了一种有价值的新工具：羧酸的直接炔基化。将特别强调该方法的广泛和方便的适用性，并将在本项目的最后阶段进行研究和论证。