The development of methods for C-C bond formation under benign conditions is an ongoing challenge for the synthetic chemist. In recent years there has been considerable interest in using selective C–H activation as a direct route for generating reactive intermediates. Herein, we describe the exploitation of the autoxidation pathway of heteroaromatic heterocycles as a simple, clean and effective method for C-H activation, resulting in the generation of a reactive nucleophilic -C-H radical. This radical can be used for C-C bond formation upon trapping with an appropriate radical acceptor species and herein we describe the application of this method for the formation of a wide variety of functionalised alkynyl and vinyl heterocycles, both of which have been shown to have broad use in organic synthesis. The aerobically-induced transformations are demonstrated to proceed robustly in a simple three component reaction mixture, utilising the unique hydrogen-bonding properties of HFIP (Hexafluoroisopropanol) as a co-solvent and deploying only five equivalents of the heterocycle as the substrate. The conditions that were developed are in sharp contrast to previous reported conditions for C-C bond formation of alkynyl and vinyl heterocyclic species, which tend to use expensive transition metals, peroxides that require thermal or photochemical degradation, or specialist photocatalysts. A large range of heterocyclic species could be functionalised using this method, not limited to 5 or 6 membered ethereal species such as tetrahydrofuran or N-protected morpholine. Sulphur based heterocycles also proved to be compatible alongside acyclic ethereal moieties. The alkynyl and vinyl handles could also be manipulated to a range of R2 groups giving access to a diverse portfolio of molecules via a simple yet powerful method. Natural product substrates such as Ambroxide and podophyllotoxin were also alkynylated. The radical mechanism of the reaction was investigated by inhibition, 13C labelling and NMR experiments, to provide a full mechanistic picture.

Exploiting dioxygen in air for free radical C-H activation of heterocycles

ACS Spring 2022

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