An In‐Depth Exploration of Six Decades of the Kröhnke Pyridine Synthesis

The Kröhnke Pyridine Synthesis has been discovered about six decades ago (1961), by Fritz Kröhnke and Wilfried Zecher at the University of Giessen. The original method involved the reaction of α‐pyridinium methyl ketone salts with α,β‐unsaturated carbonyl compounds in the presence of a nitrogen source, frequently ammonium acetate. Since its discovery, the Kröhnke methodology has been demonstrated to be suitable for the preparation of mono‐, di‐, tri‐ and tetra‐pyridines, with important applications in several research fields. Over the years, a number of modifications to the original approach have been developed and reported, enabling for the broad applicability of these methods even in modern days, also for the synthesis of non‐pyridine compounds. In this critical and tutorial review, we will thoroughly explore and discuss the potential of the original method, the refinements that have been made over the years, as well as some applications arising from each type of pyridine and/or non‐pyridine compounds produced by Kröhnke's approach. The six decades of the so‐called “Kröhnke Pyridine Synthesis” were looked over in detail, charting the reaction set‐up, mechanistic considerations and substitutions patterns, as well as the most common applications of the pyridines synthesized using the Kröhnke's method. Deviations from the standard approach are showcased, arguing the mechanistic tricks which lead to non‐pyridine compounds.