A three-step strategy for the conversion of pyridines into benzonitriles
Reyhan Güdük, Niklas Kehl, Chiara Stavagna, Michael J. Tilby, Oliver Turner, Alessandro Ruffoni, Henry P. Caldora, Daniele Leonori
Abstract
Abstract Bioisosteric replacement is a key strategy in drug discovery. Although modifying peripheral functionalities is relatively straightforward, substituting core ring structures often demands a complete synthetic redesign. Substituting benzenes with pyridines is often pursued because the nitrogen atom in pyridine can enhance biological potency and metabolic stability. Conversely, replacing pyridines with benzenes, particularly benzonitriles, can also be of value. Benzonitriles are similarly polarized to pyridines and can effectively mimic their hydrogen-bond acceptor properties. Here we introduce a strategy for converting pyridines into benzonitriles. The method uses a three-step protocol, beginning with pyridine N -oxidation, followed by photochemical deconstruction in the presence of an amine. This sequence produces a nitrile-containing butadiene, which then undergoes a formal Diels–Alder cycloaddition with alkynes and alkenes to construct the benzonitrile ring. This methodology provides a retrosynthetic tactic for the preparation of benzonitriles from pyridine-based starting materials and enables direct, modular late-stage diversification of drug molecules.