Investigations into direct N-arylation reactions

This thesis details investigations and the optimisation of N-arylation reactions using preciousmetal-
free conditions. It is an important motif in several pharmaceutical and agrochemical
molecules. In 1965 Bock et al described the use of concentrated sulfuric acid and acetic acid
as the solvent in a modified version of the Hofmann-Lӧffler-Freytag to carry out direct
amination of aromatics via N-haloamines.1
The first section looks at the UV irradiation chemistry where we utilised N-halo species which
under photolytic conditions form the aminium radicals. Several examples of
tetrahydroquinolines being synthesised in flow have been carried out.
Investigations into amination of electron-deficient heterocycles such as pyridines were also
investigated. Unfortunately, no N-arylation was observed under the various conditions trialled.
Similar investigations have been carried out into the photolysis of N-chloroamides with varying
degrees of chain length and position of the amide. Under neutral conditions in the presence of
a Lewis acid some success in N-arylation reactions has been observed.
In the second section the use of iron(II) salts has been investigated towards the N-arylation
reaction via the aminium radial generated from the N-halo species. A variety of substrates
containing electron-poor and electron-rich aromatic rings have been synthesised under these
conditions.
This methodology has been expanded to include an iron salt variant of the work with examples
of intramolecular and intermolecular direct N-arylation described. Using our methodology
some simple aromatics and the drug naproxen have now been aminated successfully. The use
of hydroxylamines as alternative precursors to the aminium radical has also been investigated
with some success in the synthesis of various substrates.