Photoredox-Active Tertiary N-Oxyammonium Reagents For Selective sp3 C-H Oxidative Functionalization

Abstract

The C(sp3)-H bond functionalization under photoredox catalysis has been a topic of active research over two last decades. Photoredox catalysis involves the use of light to access catalysts’ excited states allowing for facile single electron transfer (SET) with a hydrogen atom transfer (HAT) agent precursor. One prominent HAT agent precursor is quinuclidine (Q), of which the active radical is the electrophilic radical cation (Q●+) able to abstract a hydrogen atom from a C(sp3)-H bond, so allowing for the bond functionalization. Q has been used by researchers since 2015 in the reductive photoredox catalytic C(sp3)-H functionalization (Chapter 1). In this work we focus primarily on the design of novel N-acyloxyquinuclidinium reagents with the goal of the development of new reaction protocols for the selective oxidative C(sp3)-H bond functionalization that utilize our new reagents under photoredox catalysis. In Chapter 2 we present our new catalytic system that allows for the selective oxidative C(sp3)-H trifluoroacetoxylation of donors of 1o, 2o and 3o benzylic C-H bonds using N-trifluoroacetoxyquinuclidinium trifluoroacetate that can be conveniently generated in situ by mixing quinuclidine N-oxide and trifluoroacetic anhydride in DCM solutions. Under photoredox catalyst under blue LED light, this reagent allows for the unique high-yielding (up to >99%) selective oxidative trifluoroacetoxylation of various (functionalized) alkylarenes used as limiting reactants (22 examples overall, including a pharmaceutical-derived substrate). The proposed reaction mechanism involves Q●+ as a highly selective HAT agent and benzylic carbocations resulting from oxidative radical polar crossover of transient benzylic radicals. In Chapter 3 we introduce a series of isolable N-aroyloxyquinuclidinium tetrafluoroborates (Q-Bz) that allow for the preparation of N-alkylimides in a first of its kind Ritter-Mumm type three-component oxidative imidation of donors of benzylic and cycloalkane C(sp3)-H bonds. In this reaction carbonitriles serve as the source of an imide nitrogen atom and a solvent, whereas the third reaction component, Q-Bz, acts as the oxidant, the source of HAT agents and one of two acyl groups of the imide products. All three reaction components can be varied. 33 different N-alkylimides were prepared using (substituted) alkylarenes as limiting reagents, with product yields up to 94%, and cycloalkanes taken in 3-fold excess with respect to the oxidant. The proposed reaction mechanism involves either Q●+ or aroyloxy radicals as HAT agents, depending on the identity of the aroyl group. Chapter 4 discusses the first example of a Balz-Schiemann – type C(sp3)-H fluorination of alkylarenes and cycloalkanes using N-aroyloxyquinuclidinium tetrafluoroborates (Q-Bz), with tetrafluoroborate anion as the source of the fluorine atom of the resulting alkyl fluorides. The proposed reaction mechanism involves either Q●+ or aroyloxy radicals as HAT agents. Chapter 5 discusses the use of N-trifloxypyridinium salts for Minisci type cross dehydrogenative coupling (CDC) of alkane C-H bonds and pyridine C(sp2)-H bonds. Some limitations and possible future development of this chemistry are presented. Finally, Chapter 6 gives a summary of the results of this work and suggests future directions for the advancement of oxidative C(sp3)-H functionalization chemistry using various N-oxyammonium salts as HAT agent precursors, oxidants, and co-reagents.