Direct Access to Unprotected Primary Amines via Iron Catalysis
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Date
2022
Publication Type
Doctoral Thesis
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yes
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Abstract
Nitrogen-containing molecules, particularly amines, play crucial roles within the molecular sciences. Despite their significance throughout the scientific community, the synthesis of these target molecules is often hampered by the challenging installation of the amino group. The majority of synthetic strategies consisted of the use of pre-functionalised building blocks and tedious protecting-group manipulations. To increase synthetic simplicity and versatility, the use of abundant feedstock chemicals such as unsaturated hydrocarbons and sulfur compounds, and the installation of unprotected amino groups are highly desired. Moreover, the development of difunctionalisation reactions that install a useful functional group in the proximity of the amine would accelerate the transformation of simple building blocks into densely functionalised molecules, thus reducing synthetic steps and resources. Within this thesis, these concepts were followed and resulted in the discovery of novel amination reactions using benign iron-catalysts. First, an aminoazidation reaction was established which functioned as an unsymmetrical diamination strategy to access unprotected 2-azidoamines from alkenes in a single step. Applying this methodology, a broad range of aliphatic alkenes and vinyl arenes were successfully converted with excellent regio- and chemoselectivity. Moreover, this reaction displayed immense functional group tolerance allowing for the specific transformation of highly complex alkenyl substrates, including a tripeptide. Simultaneously, it demonstrated high tolerance towards air and moisture and good scalability, making it a practical synthetic tool. Owing to the unprotected nature of the primary amino group, these synthesised azidoamines are ideally masked, unsymmetrical vicinal diamines which allowed for sequential functionalisation of both amino groups. This behaviour could be harnessed in the (formal) synthesis of three different bioactive compounds. Mechanistically, the stereoconvergent transformation of internal alkenes, as well as radical clock experiments and the results of a Hammett-plot support a radical pathway. Furthermore, the same hydroxylamine-derived reagent was employed in an iron catalysed aminooxygenation reaction of thiols to afford unprotected, primary sulfinamides. A dual role was played by the reagent as it acted both as aminating reagent and oxidant in this transformation. This enabled the facile conversion of several aliphatic and aromatic thiols, resulting in a broad substrate scope and good functional group tolerance. Further investigations led to a proposed mechanism which featured an uncommon sulfinimidate-ester. This intermediate would result from a reaction with methanol, thus identifying the solvent as the source for the incorporated oxygen
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published
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Examiner : Morandi, Bill
Examiner : Bode, Jeffrey
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Publisher
ETH Zurich
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Subject
Catalysis; Amination; Synthesis; ORGANIC CHEMISTRY; Methodology; IRON (CHEMICAL ELEMENTS)
Organisational unit
09634 - Morandi, Bill / Morandi, Bill
Notes
Funding
184658 - Catalytic synthesis of unprotected amines and heterocycles (SNF)