Ross, Sean2020-01-102020-01-102017-11https://hdl.handle.net/11299/211320University of Minnesota Ph.D. dissertation. November 2017. Major: Chemistry. Advisor: Thomas Hoye. 1 computer file (PDF); 484 pages.The ability to thermally generate benzynes via the cycloisomerization of a tethered alkyne with a conjugated diyne (the hexadehydro-Diels–Alder reaction) allows for the generation of benzynes under neutral, reagent-free conditions. This has allowed for the study of the reactivity of benzyne, which is one of the most synthetically useful reactive intermediates, under mild, neutral conditions. The HDDA reaction has been used to study the mechanism of the addition of tertiary amines to benzyne (Chapter 3). These studies have shown that the preference for the intermediate 1,3-zwitterion to undergo an intra- or intermolecular protonation event is dependent on the nature of the amine. This mechanistic understanding allowed for the development of a three-component coupling reaction between HDDA-generated benzynes, cyclic tertiary amines, and protic nucleophiles (Chapter 4). This has allowed for the rapid and modular construction of multiheterocyle rich small molecules with drug like properties that have been submitted for biological screening. The ability of complex amines to efficiently undergo these reactions suggested that benzyne is a highly discriminating reactive intermediate. To probe the degree of selectivity with which benzyne would react with substrates containing multiple functional groups, and therefore multiple sites of reactivity, natural products were used to trap HDDA-generated benzynes (Chapter 5). These results show that benzyne is able to react with exceeding high levels of selectivity for one functional group in the presence of many others, a feature that was under appreciated. In a completely different vein, the HDDA reaction has applied to the synthesis of indenofluorenediones through the bidirectional HDDA reaction (Chapter 7). This approach allows for the rapid and flexible synthesis of indenofluorenediones and related molecules for applications in molecular electronics. Lastly, the total synthesis of selaginpulvilin C has been accomplished via the room temperature HDDA cyclization of a tetrayne precursor (Chapter 8).enHexadehydro-Diels–Alder reactionNatural product functionalizationThree-component reactionsThesis or Dissertation