Experiments and DFT Computations Combine to Decipher Fe-Catalyzed Amidine Synthesis through Nitrene Transfer and Nitrile Insertion

Multicomponent reactions are attracting strong interest as they contribute to the development of more efficient synthetic chemistry. Understanding their mechanism is thus an important issue optimize operation. However, it also a challenging task owing complexity succession molecular events involved. Computational methods have recently proven be utmost help decipher some these processes, and integrated experimental theoretical approaches appears most powerful means understand mechanisms at level. A good example given by synthesis amidines which pharmaceutical compounds. Their requires association three components, often alkyne, secondary amine, organic azide nitrene precursor. We found that alternative way offered Fe-catalyzed combination hydrocarbon, nitrile, gives in yields under mild conditions. The efficiency transformation paucity mechanistic information on prompted us thoroughly investigate its mechanism. Several scenarios were explored using techniques, including radical trap 15N labeling studies, combined with density-functional theory (DFT) calculations reaction profiles. This allowed show amidination involves trapping intermediate substrate cation Fe-released acetonitrile molecule pointing true multicomponent occurring exclusively within cage around metal center. Moreover, calculated energy barriers individual steps explained how outweighs direct amination reactions. perfect consistency between DFT results specific experiments validate them strongly supports conclusions highlights potency this approach.