Carvalho Mary-Ambre, Demin Samuël, Martinez-Lamenca Carolina, Romanov-Michailidis Fedor, Lam Kevin, Rombouts Frederik, Lecomte Morgan
Discovery Chemistry, Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
Department of Pharmaceutical, Chemical and Environmental Sciences, School of Science, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK.
Chemistry. 2022 Jan 3;28(1):e202103384. doi: 10.1002/chem.202103384. Epub 2021 Nov 5.
Nitriles are recurring motifs in bioactive molecules and versatile functional groups in synthetic chemistry. Despite recent progress, direct introduction of a nitrile moiety in heteroarenes remains challenging. Recent developments in electrochemical reactions pave the way to more practical cyanation protocols. However, currently available methods typically require hazardous cyanide sources, expensive mediators, and often suffer from narrow substrate scope and laborious reaction set-up. To address the limitations of current synthetic methods, herein, an effective, sustainable, and scalable procedure for the direct C(sp )-H cyanation of aromatic N-heterocycles with a user-friendly flow-electrochemical set-up is reported. Furthermore, high substrate and functional-group tolerance is demonstrated, allowing late-stage functionalization of drug-like scaffolds, such as natural products and pharmaceuticals.
腈是生物活性分子中反复出现的结构单元，也是合成化学中用途广泛的官能团。尽管最近取得了进展，但在杂芳烃中直接引入腈基部分仍然具有挑战性。电化学反应的最新进展为更实用的氰化方案铺平了道路。然而，目前可用的方法通常需要危险的氰化物来源、昂贵的介质，并且常常存在底物范围狭窄和反应设置繁琐的问题。为了解决当前合成方法的局限性，本文报道了一种有效、可持续且可扩展的方法，该方法采用用户友好的流动电化学装置，用于芳香族N-杂环的直接C(sp) -H氰化反应。此外，还展示了高底物和官能团耐受性，允许对药物类支架（如天然产物和药物）进行后期官能团化。
