Expedient discovery of a metallaphotoredox cyanomethylation for synthesizing α-aryl nitriles

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Cook, Gemma C. and McKay, Blandine and Jamieson, Craig and Edwards, Lee J. and Harriman, Charlotte and Read, Zackary S. and Bate, Simon T. (2026) Expedient discovery of a metallaphotoredox cyanomethylation for synthesizing α-aryl nitriles. Chemistry - A European Journal. e70946. ISSN 1521-3765 (https://doi.org/10.1002/chem.70946)

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Abstract

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.

ORCID iDs

Cook, Gemma C., McKay, Blandine, Jamieson, Craig ORCID logoORCID: https://orcid.org/0000-0002-6567-8272, Edwards, Lee J., Harriman, Charlotte, Read, Zackary S. and Bate, Simon T.;
CORE (COnnecting REpositories)