Visible Light-Driven C-H Functionalization Reactions: Methodology Design and Development of a Droplet Microfluidics Screening Platform

Abstract

The use of visible light for promoting chemical reactivity has far-reaching implications in providing access to otherwise challenging bond constructions in drug discovery, as well as minimizing the environmental impact of industrial pharmaceutical production. Along with harnessing a more sustainable energy source (e.g. sunlight), photocatalysis presents a means to circumvent the use of toxic reagents and hazardous conditions classically employed for promoting free radical chemistry in the synthesis of biologically active compounds. This thesis focuses on the development of visible light-mediated methods for the late-stage functionalization of heterocyclic drug scaffolds, as well as the design of a droplet microfluidics platform for the high-throughput optimization of photocatalytic reactions. Chapter 1 provides a detailed summary of visible light-driven methodology that have been developed to enable the C–H alkylation of biologically relevant (hetero)arenes. The application of photoredox catalysis for alkyl radical generation has given rise to a multitude of methods that feature enhanced functional group tolerance, generality, and operational simplicity. This chapter will highlight examples of visible light-driven Minisci alkylation strategies that represent key advancements in this area of research. The scope and limitation of these transformations will be discussed, with a focus on examining the underlying pathways for alkyl radical generation. Chapter 2 focuses on a method for the photoredox (perfluoro)alkylation of heteroarenes using alkyl carboxylic acid derivatives. Late-stage introduction of alkyl and perfluoroalkylated groups onto unfunctionalized positions on a drug scaffold holds significant potential for accelerating the drug discovery process. As such, the development of a visible light-driven heteroarene alkylation strategy, including optimization studies, elucidation of scope, and mechanistic studies, is described. Chapter 3 describes our efforts in developing a droplet microfluidics-based, nanoelectrospray ionization-mass spectrometry (nESI-MS) platform for screening photoredox catalysis reactions. Both the time and resource-efficient principles governing this technology underscore its anticipated impact on providing accelerated access to an array of diversified drug scaffolds using sustainable, visible light-driven synthetic methods. Application of this system towards the high-throughput late-stage diversification of complex pharmaceutical scaffolds is established in this chapter. Chapter 4 continues to explore the utility of droplet microfluidics as a platform for screening photoredox reactions in continuous flow. Here, we describe the development of a droplet microfluidic photoreactor setup that combines ESI-MS analysis to enable high-throughput reaction discovery on picomole scale. This platform is anticipated to enable the direct optimization of flow reaction parameters (e.g. flow rate, residence time) and in turn, expedite the translation of discovery scale flow conditions to pilot scale continuous flow operations. Chapter 5 discusses a microwave heating strategy for streamlining the synthesis and diversification of Ir(III)+ polypyridyl complexes for applications in photoredox catalysis. This method is envisioned to help accelerate future developments in visible-light mediated chemistry. Additionally, the synthesis of novel nanohoop ligand-bearing Ir(III)+ polypyridyl complexes is described, along with the photophysical and electronic characterization of these complexes.