Development of a Direct Alkynylation of Carboxylic Acids

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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.