Unlocking the Potential of N-O Bonds in Organic Synthesis

This thesis examines various aspects of harnessing the reactivity of N-O bond-containing molecules toward useful synthetic organic chemistry. In each chapter, the key to this challenge lies in the careful formation of energetic molecules containing N-O bonds and the controlled release of that energy toward driving the transformation of interest. To achieve this goal, high-throughput experimentation has been employed throughout the course of this research in order to maximize productivity and learning while simultaneously minimizing time and material requirements. Enabled by these tools, this thesis is the result of almost 14,000 experiments. Chapter 1 describes the iron-catalyzed synthesis of indoles from ortho-nitrostyrenes. Mechanistic studies revealed that the iron-phenanthroline catalyst serves to shuttle oxygen atoms from nitro groups to silanes in order to generate reactive ortho-nitrosostyrenes, which then undergo spontaneous 6π-electrocyclization and subsequent reduction to give indoles. Chapter 2 describes the synthesis of furo[2,3-b]indolines from N-hydroxyindoles in a reaction cascade sequence. Key reactive N-alkenyloxyindole intermediates are formed from conjugate addition of N-hydroxyindoles to activated alkynes with catalytic base, and then spontaneously undergo [3,3]-sigmatropic rearrangement and cyclization to form the product heterocycles. Chapter 3 describes the mechanistic study of solvent effects on the [1,4]-4π-electrocyclizations of N-alkenylnitrones and the development of the first example of a catalytic asymmetric [1,4]-4π-electrocyclization. Eyring analysis of activation parameters for the thermal electrocyclization of N-alkenylnitrones was conducted in order to identify solvents with minimal background reactivity that can also solubilize the cationic (MeCN)4Pd(BF4)2 / phosphine catalysts needed to promote enantioselective [1,4]-4π-electrocyclization to form 2,3-dihydroazete-N-oxide products.