Catalytic hydroarylation of alkenes is an attractive alternative to Friedel–Crafts type reactions of alkyl halides for the alkylative functionalization of aromatic C–H bonds. Many catalytic hydroarylations of alkenes are known, but few of them efficiently afford quaternary carbons from 1,1-disubstituted alkenes. Quaternary carbons are difficult to synthesize due to their sterically congested nature, which can lead to kinetic barriers to formation and thermodynamic instability. Herein, we report an efficient and highly selective methodology to intermolecularly functionalize trifluoromethylated (and other electron-deficient) α-methyl styrenes with a variety of aromatic compounds through the action of a tritylium precatalyst. This method gives access to a wide range of diaryl-dialkyl quaternary centers. Recent research into the reduction of alkene/alkyne to an alkane using B–B bond-containing reagents, such as B2(OH)4 and catalytic amounts of palladium on carbon, can mediate transition metal-catalyzed H atom transfer from H2O, leading to the reduction of alkenes and alkynes under mild conditions. Very few experiments for an introductory undergraduate organic chemistry lab demonstrate an alkene/alkyne to alkane reaction using transition metals. For this experiment, Palladium acetate was selected as the catalyst, an electron-rich alkene trans-stilbene was selected because of its ease to measure and to ensure the reaction could go to completion within the time constraints of a typical lab, which is 2-MeTHF was used as the solvent to increase the speed of completion of the reaction to an hour.

The following dissertation discusses the development of Selectfluor mediated Minisci reactions leading to functionalized heterocycles and quinones. These investigations include a wide variety of heterocycles and quinones that can be functionalized in one step allowing for access to more complex structures while retaining the essential backbone. Mechanistic investigations and direct comparisons to other harsher oxidants are considered. Novel transnitrosating reagents were developed allowing for nitroso compounds in one step when thermally initiated. Considerations for other applications for this novel reagent are discussed as well.

Benzylic C–H bonds are ubiquitous in pharmaceutical and other biologically active compounds. The low BDE of the benzylic C–H bond has made it a target for further functionalization, where the original bond may be replaced with a C–C bond, C–O bond, C–N bond, or C–X bond, (where X = halogen). While the functionalization of benzylic C–H bonds to C–C/O/N bonds are relatively well established, selective halogenation proves to be more challenging. Halogenation typically refers to chlorination, bromination, and iodination, but has recently come to include fluorination. Achieving fluorination has traditionally been cumbersome. Classical methods of generating a C–F bond typically require harsh conditions with highly toxic reagents. C–F bond formation has increasingly become of interest primarily for its advantageous biological features. The focus of this dissertation will be method development and mechanistic investigation of silver(I)-catalyzed benzylic C–H fluorination via radical pathways.

Recent developments of new fluorinating reagents have afforded methods that no longer require highly toxic chemicals; however, current radical fluorination still require harsh reagents, (e.g. strong oxidants), or have a limited substrate scope. Utilizing the idea of radical decarboxylative fluorination, and the demonstrated utility of radical decarboxylation of unprotected amino acids, a novel radical decarboxylative benzylic fluorination pathway was designed where unprotected amino acids were used as radical precursors to facilitate HAT at the benzylic site, and ultimately allow for subsequent fluorination.

Upon further mechanistic investigation of the unprotected amino acids system, it was found that radical benzylic fluorination was achievable in the absence of an amino acid, so long as a free nitrogen-bearing compound, such as pyridine, was present. Through experimental and theoretical investigations, it was proposed that halogen bonding between the pyridine and fluorinating agent was facilitating the more efficient radical benzylic fluorination pathway by producing a stronger HAT agent.

Halogenation has become of great interest. Recent studies show the biological advantages when pharmaceuticals contain various halogen-carbon bonds. Halogenated compounds are used in metal-catalyzed cross-coupling reactions, pesticides, and natural products. Previously, our lab has reported radical benzylic C-H fluorination using Selectfluor, as a mild oxidant and fluorine source, in the presence of unprotected amino acids and Ag(I). In doing control reactions, we found that N-protected amino acids did not yield any product, suggesting free nitrogen was required. In contrast to the amino acid/Ag(I) method, we found that a carboxylate group was not required as long as a free nitrogen additive, such as pyridine. Herein, we report an effective method for C-H fluorination via halogen-bonding between Selectfluor and monosubstituted pyridine additives. Computational and NMR studies showed that the Lewis basicity of the pyridine additive must be optimum for halogen-bonding but not strong enough to promote unwanted side reactions.

Using this knowledge, we expanded this strategy to include C-H bromination using N-bromosuccinimide. During the initial investigation, we discovered aromatic bromination was favored over benzylic. While optimizing the reaction conditions, we determined lactic acid was an efficient catalyst for aromatic bromination. Several lactic acid derivatives were investigated and found to affect the efficiency of aromatic bromination via halogen-bonding interactions. This method gives access to a relatively less toxic procedure using catalytic mandelic acid under aqueous conditions at room temperature.

The last chapter of this dissertation depicts the development of an alternative method for halohydrin formation of alkenes. Several brominating reagents were assessed, and the best for this reaction was N-bromosaccharin. Through experimental investigations, it was determined that the carbonyl in the substrate was essential for the halohydrin formation to occur. Future work will further explore the reactivity of the carbonyl oxygen.

Chapter 2 is work adapted from J. Org. Chem. 2022, 87, 8492-8502.