Thermally accessed carbenes and benzynes derived from alkynes as a platform for synthetic methodology development

Abstract

1H NMR (proton nuclear magnetic resonance) spectroscopy is the most widely used tool for the identification and characterization of organic compounds. Accurate referencing of 1H NMR data is particularly important for comparison of spectra of different samples of the same substance. In my first research project, I compared the effectiveness, and therefore accuracy, of the most common 1H NMR reference compound, tetramethylsilane (TMS). My findings explicitly show that TMS is a superior reference compound compared to the residual CHCl3 that is often referenced when using CDCl3 solutions (Chapter 1).The hexadehydro-Diels–Alder (HDDA) reaction is the thermal or photochemical cycloisomerization of a poly-yne system to produce an o-benzyne intermediate. The fleeting o- benzyne is trapped in situ to afford benzenoid products. Given the paramount importance of heterocycles in modern drug discovery efforts, there has been a growing impetus to incorporate heterocycles into the framework of HDDA chemistry. From this perspective, I was curious to study the reactivity of oxadiazoles with HDDA benzynes, and consequently I discovered novel oxadiazole reactivity, producing a series of 2:1 adducts (Chapter 2). Alkynes may also be used as precursors for the generation of free carbenes, another type of high-energy, fleeting intermediate. Few examples of alkyne-derived free carbene generation have been reported. However, in 2024, Xu and Hoye demonstrated the broad synthetic utility of heteroaryl free carbenes, produced by the formal (3+2) cycloaddition between 2-alkynyl iminoheterocycles and electron-deficient alkynes. I expanded upon this work, showcasing how this 100% atom economical carbene methodology could be applied to the synthesis of complex, polycyclic cyclopropanes (Chapter 3). During the cyclopropanation study, I unexpectedly isolated a product arising from an intermolecular formal C–H insertion into a terminal alkyne. In recognizing that intermolecular trapping of free carbenes could be broadly applied to a host of trapping functionalities, I capitalized on this idea and developed a three-component coupling methodology in which free carbenes can be trapped by terminal alkynes, N-Boc carbamates, and amides (Chapter 4).