Taming Highly Reactive Species for Use in Organic Synthesis

Abstract

Chemical processes and reactions are never perfect; there are always some problems in scope, scalability, applicability or safety. Sometimes, if these limitations pose a seemingly insurmountable barrier to the chemistry’s overall usefulness, decades can go by without a single new development even in fields that were initially very promising or popular in their infancy. By looking back on these forgotten topics through the lens of modern technology, new cutting-edge materials and methods can be applied to solve the problems that posed too great a challenge in previous decades. In this thesis, two such examples of reactions initially discovered and developed around the late 1960’s and remained largely untouched ever since will be explored. Chapter 1 will describe the use of ozone as an oxidant to transform amines into the corresponding alkyl nitro species. Ozone is a very powerful oxidant but tends to overreact with most organic substrates, which significantly reduces its potential as a commonplace synthetic tool. These limitations in applicability stem from an inherent lack of control over the reaction, which is the issue that we sought out to address. By applying modern principles of flow chemistry, the functional group tolerance of this oxidation reaction has been drastically increased from its initial state of simple small hydrocarbons. Chapter 2 will follow a similar narrative involving the use of ‘super-bases’ to activate benzylic C-H bonds and generate a variety of benzyllithium species. Organolithiums have also had historic issues with tolerance in transition metal-catalyzed cross coupling reactions. With a surge of new publications addressing this issue by using principles of flow chemistry, there remains a lack of easy methods to generate organolithium nucleophiles as coupling partners. Generation of benzyllithiums from toluene derivatives has historically been limited to require solvent quantities of substrate, along with unreasonably long reaction times at cryogenic temperatures. By utilizing modern tools and synthetic strategies, an easy and streamlined path from toluene derivatives to organolithiums for direct use in cross coupling has been developed.