UC San Diego

The triphenylmethyl radical was first discovered and isolated by Moses Gomberg at the University of Michigan in the year 1900. The prospect of an isolable carbon-centered radical as described by Gomberg blew open the door to a whole new realm of chemistry and helped pave the way for modern organic synthesis. Now nearly 120 years past this initial discovery, radical reactions are common place in all areas of organic synthesis, and new methods are continuously being developed that utilize open shell species. Radical-mediated methods are complimentary to traditional, two-electron pathways in that they are uniquely tolerant of otherwise reactive polar functionalities.The first chapter of this manuscript describes our development of a new method for the intermolecular hydroamination of alkenes using N-hydroxyphthalimide (NHPI). Owing to the impressive oxophilicity of trivalent phosphorus, we were able to generate reactive phthalimidyl radicals via phosphorus-mediated homolytic cleavage of the N-O bond in NHPI. The installation of the phtalimidyl moiety is highly advantageous, as it can be easily removed via simple hydrolysis to provide an overall, formal-ammonia hydroamination for the production of primary amines. During the course of our investigation, we determined that this process occurred through an atom-transfer radical addition (ATRA) type mechanism wherein NHPI was used to supply both the nitrogen and hydrogen atoms for the overall hydroamination. The second chapter of this manuscript describes an extension of the ATRA capabilities of our hydroamination method in the form of an aminoallylation of alkenes using allyl-oxy phthalimides. By substituting the hydrogen atom of NHPI with an electron deficient allyl group, we took advantage of predictable radical polarity effects to invoke an overall alkene difunctionalization by way of a group transfer radical addition (GTRA). This provided further evidence for an ATRA-type mechanism for our hydroamination method, and similarly reinforced the guiding effects of proper radical polarity matching. The third chapter of this manuscript discusses our development of a method for the formal conversion of phenols to anilines utilizing an intermediary hydroxamic scaffold. Again taking advantage of the oxophilicity of trivalent phosphorus, hydroxamic acids were unmasked to reveal reactive amidyl radicals capable of performing an intramolecular, ipso-substitution at the phenolic carbon of the hydroxamic acid substrate. In comparison to traditional SNAr processes, our method was not limited to electron deficient arenes, but tolerated electronically rich substrates as well. The fourth and final chapter of this manuscript transitions away from radical amination strategies enabled by phosphorus(III)-mediated O-atom transfer, and instead describes our efforts to utilize thiyl radicals as cite-selective H-atom abstraction reagents. During the course of our investigation, we found that we could perform a thiol-catalyzed, aerobic debenzylation of amines and alcohols using pentafluorothiyl radical as the active abstracting species. This process uses only a substoichiometric quantity of thiol, air as the only oxidant, and operates in the presence of functional groups that would otherwise be intolerant of traditional benzyl-deprotection methods.