Expedient Discovery of a Metallaphotoredox Cyanomethylation for Synthesizing α-Aryl Nitriles

The α-aryl nitrile motif is a valuable pharmacophoric feature in medicinal chemistry. However, current synthetic methods to prepare this moiety frequently employ harsh reaction conditions, highly toxic cyanide reagents, or have a limited substrate scope. To address this, a mild photocatalytic cyanomethylation reaction was developed, employing an iridium/nickel metallaphotoredox system in conjunction with supersilanol, cyclopropyl bromide and a mild base, and blue light. To identify a robust set of conditions to efficiently couple acetonitrile to a range of aryl bromides, extensive High-Throughput Experimentation (HTE) was first applied. Subsequently, Design-of-Experiments (DoE) scoping and then screening experiments were performed to identify significant factors and interactions. Due to evidence of non-linear effects, this was followed by an optimization experiment using a central composite design. Finally, to confirm the conditions identified, a robustness DoE study was performed. The methodology demonstrated tolerance to a variety of functional groups, and was applicable to a range of medicinally-relevant building blocks through library synthesis. The reaction was also applied to the multigram preparation of a key anti-cancer Senexin intermediate, which shortened the synthetic route and obviated the need for a cyanide reagent.