Novel Coupling Reactions Utilizing Base Metal and Photoredox Catalysis

Abstract

Novel coupling reactions have an inherent interest amongst the practitioners of molecular construction. This strategy allows for a convergent strategy towards synthetic routes, resulting in faster syntheses. This is especially true if novel couplings can be developed utilizing catalysis. As such, an important goal in organic synthesis is the development of these reactions.

The α-amino carbonyl is a valuable motif in the pharmaceutical industry. However, The direct construction of this motif to construct has remained challenging. As a result, numerous methods have used electrophilic sources of nitrogen atoms to install the C–N bond, and elaborated substituents on the nitrogen atom. In Chapter 2, a method detailing the direct construction of this motif with elaborated nitrogen fragments is discussed. This functions via copper catalysis, and this studied culminated in the one step synthesis of the drug Plavix.

Photoredox catalysis has emerged as a mild platform towards activating common functionalities towards coupling reactions. Recently, a method detailing a decarboxylative arlyation emerged from our group in collaboration with the Doyle group. This methodology relied on both photoredox and nickel catalysis to forge the desired motif. In chapter 3, this methodology is reexamined to address several shortcomings of the seminal initial report. A more general protocol for carboxylic acids was developed. Furthermore, the scope of heteroaryl halides was also expanded and a more radical resistant photocatalyst was designed. The combination of nickel, phororedox, and hydrogen-atom-transfer catalysis is discussed in Chapter 4, as applied to a C–H alkylation. This method allows for a site-selective alkylation of a sp3 C–H bond to form a sp3-sp3 C–C bond.

Another valuable motif is the trifluoromethyl group. While there have been many elegant advances in the last decade for the installation of this challenging motif, the formation of sp3 C–CF3 bonds has remained difficult. In Chapter 5, a decarboxylative trifluoromethylation is discussed, that furnishes the desired sp3 C–CF3 bond. This is still under the initial stages of investigation, but promising results are disclosed.