Development of a Direct Alkynylation of Carboxylic Acids

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盖，从而导致额外的合成步骤。在许多情况下，醛是直接或间接地由羧酸衍生物得到的。因此，如果羧酸能直接转化为炔烃，那将是可取的。然而，尽管有巨大的合成潜力，这种方法至今仍不为人所知，因此构成本项目的目标。我们的策略是基于功能化C(sp3)-亲核试剂的设计。这些试剂应与原位活化的羧酸进行交叉偶联，并传递易于发生分子内环化的中间体。由此产生的环状化合物应依次能够进行裂解反应以释放所需的炔和高度稳定的副产物，这为这一关键步骤提供了所需的驱动力。尽管到目前为止，所提出的试剂和目标的总体过程都没有被描述，但本项目中提出的文献类比和理论调查表明，每个单独的步骤原则上应该是可行的。通过对所提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，将从羧酸活化到裂解的所有步骤统一起来，从而为合成有机化学提供一种有价值的新工具：羧酸的直接烷基化。将特别强调该方法的广泛和方便的适用性，这将在本项目的最后阶段进行研究和演示。

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.