Synthesis of N-Heterocycles and Thiocines via Electrophilic Divalent Reactive Intermediates

The formation of C–N bonds is a critical transformation in organic chemistry due to their high prevalence in structurally diverse natural products and pharmacologically active compounds. The synthesis of N-heterocycles is interesting and synthetically challenging which has motivated the work of the Driver group. My research has focused on using aryl amines and azides as the N-atom source to synthesize these complex organic scaffolds that possess biological activity such as dibenzazepines, benzimidazoles, and 3H-indoles by accessing electrophilic divalent intermediates. I found that exposure of ortho-substituted aryl amines to either 1.1 equivalents of PIFA or PhIO at room temperature triggered iminoiodinane formation, followed by C–NAr bond formation to yield dibenzazepines. The use of hypervalent iodine reagents motivated me to examine the possibility of using the same reactivity to achieve sp3-C–NAr bond formation. An iodine(III)-catalyzed process was developed using 0.5 mol % of iodobenzene, 2.3 equivalents of Selectfluor, and 2.3 equivalents of trifluoracetic acid to promote the formation of benzimidazoles. Kinetic isotope effect mechanistic studies suggested that benzimidazole formation occurs through oxidation of the piperidine nitrogen followed by an intramolecular product-determining E2 elimination. The emergence of electrochemistry as a novel way to achieve chemical transformations replacing chemical oxidants with electricity intrigued me to explore this new method. I discovered that 3H-indoles could be formed from ortho-substituted azides using graphite as both the cathode and anode and triethyl amine as an electrolyte in an undivided chemical cell. Another focus of my PhD research was to leverage the reactivity of electron-rich carbenes to construct medium-sized heterocycles. A Ru(II)-catalyzed carbene transfer reaction was discovered to construct thiocines from diazo compounds and 2-vinyltetrahydrothiophenes. Together, I was able to harness the reactivity of electrophilic divalent intermediates to develop a suite of methods to construct important N-heterocycles and carbocycles.