Mechanistic investigations and applications of the copper-catalysed azide-alkyne cycloaddition

The emergence of ‘click chemistry’ at the turn of the 21st century marked a significant methodological shift away from extensive linear syntheses towards more simplistic, modular pathways involving heteroatomic linkers. The success of this Nobel prize winning chemistry has been epitomised in the famed copper-catalysed azide-alkyne cycloaddition (CuAAC), with one of the pioneers of the methodology, K. Barry Sharpless, describing it as the “cream of the crop” of click reactions. Whilst the widespread utility of this reaction is irrefutable, a more interesting discussion resides over the mechanistic nuances involving the oxidation state of the copper catalyst. In addition to the generally accepted bi-metallic Cu(I) process reported by Fokin and colleagues, this work describes an alternative Cu(II)-promoted route to obtain identical 1,4-disubstituted 1,2,3-triazole products. This involves initial findings based upon a model substrate (2-ethynylpyridine), outlining the methods employed to ascribe Cu(II)-based activity, as well as a proposed reaction mechanism (with computational support). Developing this, several other alkynes were examined through this lens, helping to establish a mechanistic continuum with respect to the role of Cu(II) across CuAAC reactions for different substrates. The activity of various azide scaffolds was also screened. Preliminary investigations on a small molecule model have also indicated that a distinctly Cu(II)-promoted CuAAC reaction may lessen oxidative degradation of biological motifs (guanosine) when compared to traditional Cu(I)-based approaches. This work also outlines the development of a one-pot, copper-catalysed process converting simple styrene motifs to arylethylamine triazole products. This procedure combines three distinct mechanistic steps (aziridination, aziridine ring-opening, and CuAAC) and provides a streamlined access towards complex motifs with three points of diversification (styrene, alkyne, and iminoiodinane). From the developed one-pot procedure, 27 arylethylamine triazole products were accessed – including four analogues of drug scaffolds reported across the literature. This affirmed the utility of the process in facile access towards medicinally desirable targets.