Amidine Syntheses from Classic to Contemporary for Medicinal Lead Compounds and Natural Products

For close to 150 years, the Pinner reaction between nitriles and amines dominated the syntheses of amidines. Today, the Pinner reaction remains highly over‐represented in recent syntheses of unsubstituted or simple amidines. However, a number of greener amidine syntheses unlock access to more complex, highly substituted amidines, or closely related derivatives such as N ‐sulfonyl amidines. This review surveys recent advances in amidines and related compounds, including methods to install them and bioactive molecules prominently featuring the amidine functionality. Complex amidines are readily synthesized using both traditional and multicomponent reactions, which often involve metals. Recent trends include metal‐free methodologies and expanded structural diversity of amidine products. The second half of this article reviews the utility of amidines as carbonyl bioisosteres for natural products, functional linkers, or as a bioactive functional group. The biological activities of recently reported amidine‐based compounds will be surveyed with an emphasis on promising antibacterial and antiproliferative compounds.