Applications of organochalcogen catalysts in C-H amination and substitution reactions

Abstract

The field of C-H activation has been dominated by transition metal catalysis, especially in the formation of new C-N bonds. However, these complexes can be costly, often require arduous syntheses, and can be air and moisture sensitive. Vast amounts of research have been undertaken to elucidate selectivity in these pathways, but there remain regioselectivity and chemoselectivity obstacles to overcome. To avoid the unproductive side reactivity of transition metal complexes, to access structures orthogonal to those available, and to develop more easily tuned catalysts, the Michael Lab has spent tremendous effort in exploring organochalcogen compounds as alternatives to transition metal complexes. During our exploration, we found that in addition to oxidative chemistry, these compounds are competent nucleophiles able to form chalconium salts in situ. This observation revolutionized the way our lab thought about phase-transfer catalysis, precluding the need to use premade hygroscopic and difficult to recover salts. This dissertation presents work aimed at advancing the capabilities of organochalcogen species in the context of propargylic C-H amination, directed allylic C-H amination, and -onium salt phase-transfer catalysis. The first method discussed is the intermolecular propargylic C–H amination of alkynes. This reaction is transition metal-free, instead relying on phosphine selenide catalysts. Terminal, silyl, and internal alkynes containing a variety of functional groups were aminated in high yields. Mechanistic studies revealed that the proposed ene reaction has a transition state that results in partial positive charge build-up at the carbon atom proximal to the C-H being activated. This allowed inductive and/or hyperconjugative stabilization or destabilization of this positive charge to direct regioselective C-H amination. Next, a selenium catalyzed allylic C−H amination reaction of vinylsilanes and vinylboranes is discussed. These substrates are ubiquitous in organic synthesis, but direct functionalization of these species without the participation of the C−Si or C-B bond is rare. Due to the metal-free nature of this protocol, a new C-N bond can be installed without competing transmetallation or alkene addition reactions. In this transformation, the silicon or boron substituent inverts the usual regioselectivity, directing amination to the site distal to that group. Subsequent cross-coupling or demetallation allows access to complementary regioisomeric products. Finally, organochalcogen-catalyzed phase-transfer reactions are discussed. Contrary to traditional phase-transfer protocols which commonly rely on an exogenous catalyst to affect the solubility of reactants, the relevant ionic species is generated in situ via nucleophilic displacement of a variety of alkyl leaving group by chalcogen imidazole compounds. This mode of reactivity was studied in a wide range of non-polar and polar solvents allowing both solid-liquid and liquid-liquid phase transfer reactions with anionic nitrogen, oxygen, and sulfur nucleophiles. The neutral catalyst was easily recovered and recycled in opposition to conventional salts.