Novel Reactions of Free Radicals: Key Intermediates for the Construction of C-N Bonds

UoM administered thesis: Phd

  • Authors:
  • Lucrezia Angelini

Abstract

Nitrogen-containing compounds are ubiquitous in a myriad of natural products and bioactive molecules. Methods for their construction are therefore fundamental in synthetic chemistry. The construction of valuable C-N bonds via radical chemistry has been relatively less explored compared to the classic electrophilic and nucleophilic amination strategies. This has to be attributed to the harsh conditions usually needed to access reactive radical intermediates. Radical strategies represent a powerful tool in the realm of synthetic chemistry as these have the potential to complement classic ionic strategies and overcome their common limitations. This thesis will discuss novel methodologies to forge key C-N bonds exploiting the chemistry of carbon (CCR) and nitrogen centred radicals (NCR). Initial work used nucleophilic CCRs in combination with nitrosoarenes SOMOphiles to access aryl hydroxylamines under photoredox conditions. CCRs were generated upon photoinduced single electron oxidation-fragmentation of commercially available carboxylic acids in the presence of a base and an organic photocatalyst under visible light irradiation. This procedure represents one of few examples of utilization of nitrosoarenes as radical trap in radical synthetic amination strategies. Next, NCRs from electron-poor O-aryl-hydroxylamines were coupled for the first time in a nickel-catalysed umpolung amination with different organometallic reagents. Key to the success of this strategy is the ability of nickel(I) to promote single electron reduction of the NCR precursor in the ground state. Exploiting the different philicity of aminyl, amidyl and iminyl radicals, three different transformations were developed, including N-arylation, cascades amino-arylation/alkylation and ring opening-functionalization. Finally, a methodology for the construction of vicinal di-amines was developed. This method relies on the sequential formation of two C-N bonds from an olefinic C=C double bond using a radical and ionic synergic strategy. First, the formation of ambiphilic b-chloro- alkylamines were obtained through a photoinduced radical chain reaction using in situ generated N-chloroammonium species, simple olefins and a photoinitiator. These b-chloro- alkyl amines were then reacted in situ with a second nucleophilic amine via the formation of a reactive aziridinium intermediate. This methodology was applied to the synthesis of highly functionalized di-aminated molecules.

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Original languageEnglish
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Award date31 Dec 2021