Understanding C-H bond functionalisation at heterocycles and biomolecules: a synthetic and mechanistic study

The Pd-, Cu- and Pd/Cu-mediated direct functionalisation of C2-H bonds at 1,3-X,N-heterocycles (where X = S, O, N) and indole-containing biomolecules has been investigated. Such processes are useful in the synthesis and labeling of complex molecules, and represent an improvement on traditional Pd-mediated cross-coupling. A study of the mechanism of C2-H bond functionalisation of 1,3-X,N-heterocycles (specifically benzimidazole, benzothiazole and benzoxazole) with Pd/Cu catalyst systems has indicated a key role for Pd0 nanoparticles. Nanoparticles have been demonstrated to form in situ when molecular PdII pre-catalysts are employed, and have been characterized by transmission electron microscopy (TEM). The catalytic activity of these nanoparticles has been shown to vary with reaction environment (e.g. the use of different reaction vessels). Pre-synthesised, well-defined Pd0 nanoparticles supported on polyvinylpyrolidone (PVP) are effective catalysts for these processes and increase reaction reliability. It is proposed that Cu N-heterocarbene(NHC) intermediates play a key role in these processes. A model system {(1,3-dibenzyl)benzoimidazolylidenecopper(I) bromide} has been synthesised using an electrochemical method. The reaction of this model with PhI within and without the presence of PdII results in arylated product. Whilst conducting these studies, the novel compound bis{(1,3-dibenzyl)benzimidazolium}dicopper(I)tetrabromide was isolated. The C-H bond functionalisation of benzoxazole with a Pd/(1,10-phenanthroline)catalyst and PhI(OAc)2 aryl source has been studied in detail. Pd0 nanoparticles have isolated and characterized from this reaction. It has also been demonstrated that PhI(OAc)2 rapidly degrades to PhI under the reaction conditions. The indole-based amino acid tryptophan is fluorescent, and modifying this fluorescence is of interest. A mild and selective C2-H bond functionalisation reaction for this amino acid has been developed, both as a single residue and within peptides. NMR spectroscopy, ReactIR® and other techniques have been used to build up a mechanistic picture of this reaction, with is proposed to proceed via a Pd0/II manifold.