The Hexadehydro-Diels-Alder (HDDA) Benzynes with Nitrogen-Nucleophiles (Diaziridines, N-Hetaryls, and C,N-Diarylimines); and the Kobayashi Benzynes as HDDA-Diynophiles

Abstract

Nitrogen heterocycles (N-heterocycles) are among the most significant structural components of today’s pharmaceuticals. According to a perspective article in Journal of Medicinal Chemistry, 84% of the drugs available in the current market have at least one nitrogen atom present in them. More significantly, 59% of the total FDA-approved drugs contain at least one nitrogen heterocycle. These data are compelling and motivate a chemist to creatively develop numerous synthetic strategies that can be used for (i) construction of new N-heterocycles from simple starting materials and (ii) functionalization (i.e. modification) of known N-heterocycles.A major portion of my thesis research (Chapter 2, 3, and 4) is guided by these two ideas. In my quest to achieve these goals, I have used a reaction as a tool, which is called the hexadehydro-Diels–Alder (HDDA) reaction. This reaction is a valuable new variant of the Diels–Alder reaction, which is found in every introductory organic chemistry textbook. The HDDA reaction operates in a purely thermal (and therefore milder) environment to generate benzynes, which are one of the most reactive intermediates in organic chemistry. I have reacted the benzynes that were generated via the HDDA reaction with (i) diaziridines (chapter 2), (ii) six-membered N-hetaryls (chapter 3), and (ii) C,N-diarylimies (chapter 4). In many instances, these thermally generated benzynes allow for the formation of the nitrogen-containing trapping products in a much cleaner and unique manner. In the later section (chapter 5) of the thesis, I will demonstrate the utility of classically generated benzynes as a diynophilic partner in the HDDA reaction. This reaction requires only mildly basic and ambient temperature conditions and allows for rapid construction of various naphthalenic products