Part I: development of dirhodium-catalyzed intermolecular C-H amination; part II: synthesis and applications of sulfamate esters
- Nicholas D. Chiappini.
- [Stanford, California] : [Stanford University], 2019.
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- Catalytic methods for C(sp3)--H amination are enabling technologies for both the synthesis and late-stage diversification of myriad organic molecules. Contemporary challenges that propel future development of such processes are presented by complex substrates approximating the architectures found in natural products along with polar, functional group-rich active pharmaceutical and agrochemical ingredients. In our efforts to address these limitations, we have established a catalytic system for C--H amination that markedly advances the ability of chemists to efficiently introduce nitrogen into molecules of different structural types. The discovery of pivalonitrile (t-BuCN) as a differential solvent for Rh-catalyzed intermolecular amination of C(sp3)--H bonds and phenyl sulfamate (PhsNH2) as a nitrene precursor has enabled efficient functionalization of a wide variety of complex molecule substrates including natural products and active pharmaceutical ingredients (APIs). Although limitations remain with oxidatively labile functional groups, including basic amines, our disclosure represents a definitive leap forward in the state-of-the-art for C--H bond oxidation. Mechanistic data strongly implicate a pathway for catalyst decomposition that initiates with solvent oxidation, thus providing rationale for the marked influence of pivalonitrile on this reaction process. The phenyl sulfamate nitrogen source can be unmasked under mild conditions using pyridine and water to unveil the corresponding primary amine products. Additionally, through amination of bromoalkane and mesyloxalkane substrates, SN2 cyclization can afford azetidines and other saturated azacycles in good to excellent yield. In pursuit of alternative, modular methods for the installation of sulfamate and sulfamide groups, we have developed pentafluorophenyl sulfamate (PfpsNH2) and trichlorphenyl sulfmatate (TcpsNH2) as bench-stable, versatile reagents for sulfamoylation of alcohol and amine nucleophiles to generate N-unsubstituted sulfamates and sulfamides. This type of 'click' reaction should find widespread use in academic and industrial labs.
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- Submitted to the Department of Chemistry.
- Thesis Ph.D. Stanford University 2019.