Fine-Tuned Imino-Diels–Alder Reaction for the Sustainable Synthesis of Nicotinonitriles via Push–Pull Vinylogous Enamino Nitriles

Nicotinonitriles are valuable bioisosteres of nicotinic acid demonstrating diverse biological activities, but mild and versatile synthetic methods remain elusive. Imino-Diels-Alder reaction has been used as a pivotal tool in preparing nitrogen-containing heterocycles, such as pyridines. However, existing strategies for the imino-Diels-Alder reaction have suffered from challenges such as installing a nitrile at the C3-position of pyridines and preventing undesired autoxidation leading to 3-hydroxypyridines. Herein, we demonstrate an acid- and metal-free imino-Diels-Alder reaction between vinylogous enaminonitriles and iminium salts, providing access to 2,4-disubstituted nicotinonitriles. Aromatization proceeds smoothly under air/TEMPO conditions, which effectively suppress undesired autoxidation. The operationally simple one-pot protocol employs reusable ethanol as solvent, equimolar reagents and a substoichiometric TEMPO, minimizing waste. Vitamin B₃ and 3-aminopyridine derivatives can also be accessed through simple modifications of nicotinonitriles. This strategy features characteristics of sustainable chemistry and, moreover, highlights the potential of vinylogous enaminonitriles as activated dienes in hetero-Diels-Alder reaction while circumventing the limitations of existing synthetic approaches.