IRON-CATALYZED SUZUKI-MIYAURA CROSS-COUPLING: FROM FUNDAMENTAL ORGANOMETALLIC CHEMISTRY TO CATALYSIS

Abstract

The Suzuki-Miyaura cross-coupling reaction is critical for the construction of carbon-carbon bonds in a variety of chemical contexts, including in the pharmaceutical industry. However, while the Suzuki-Miyaura reaction is highly effective, the commonly employed palladium-based catalysts are expensive, toxic, and have a high global warming potential associated with their production. In contrast, iron-based cross-coupling catalysts are attractive due to the abundance, low cost, and extremely low toxicity of iron. Moreover, exploration of iron-based catalysts allows for development of new types of reactivity, including the incorporation of different variants of nucleophiles and electrophiles. However, iron-catalyzed Suzuki-Miyaura cross-coupling is significantly less developed than palladium-based methods and has principally relied on pre-activated anionic boronate nucleophiles and harsh coupling conditions. Therefore, the development of understanding of iron-based catalysts for cross-coupling represents both a fundamental challenge and a significant advance towards the development of green chemistry. The first part of this dissertation will first describe the development of fundamental organometallic chemistry relevant to iron-catalyzed Suzuki-Miyaura cross-coupling. Specifically, the three canonical steps of palladium-catalyzed cross-coupling have been demonstrated with iron. In Chapter 1, the transmetalation of aryl boron reagents to pyridine(diimine) iron alkoxide compounds is demonstrated, and the neutral transmetalation pathway is shown to be viable. In Chapter 2, the oxidative addition of aryl and alkyl halides to a reduced iron pincer complex is demonstrated, and the mechanism of oxidative addition is investigated. In Chapter 3, the reductive elimination of carbon-carbon bonds from iron pincer compounds is demonstrated, and conditions to favor reductive elimination are developed. In the second part of this dissertation, a catalytic cross-coupling method was developed using insights gained from the first three chapters. Chapter 4 details the development of a method for iron-catalyzed Suzuki-Miyaura C(sp2)-C(sp3) cross-coupling using a new class of phenoxyimine iron alkyl precatalysts. This method employs neutral boronic ester reagents and alkoxide bases, both commonly found in palladium-catalyzed methods for cross-coupling, but unprecedented with iron. Finally, Chapter 5 details mechanistic understanding of the transmetalation step in the catalytic method and provides an understanding for how to favor aryl transmetalation to iron in catalysis.