Hantzsch Dihydropyridine Synthesis

In 1882, A. Hantzsch condensed two equivalents of ethyl acetoacetate with one of acetaldehyde and ammonia to obtain what he believed at the time to be a 2,3-dihydropyridine but was later found to be a 1,4-dihydropyridine. Since then, the one-pot condensation of a beta-keto ester or a 1,3-dicarbonyl compound with an aldehyde and ammonia to prepare 1,4-dihydropyridines is known as the Hantzsch dihydropyridine synthesis.

Often the 1,4-dihydropyridines spontaneously oxidize to the corresponding substituted pyridines, but in the case of more stable variants, oxidizing agents are used as necessary, e.g., HNO₂, HNO₃, MnO₂, etc.

The original procedure only provided symmetrical products. However, several modifications afford unsymmetrical dihydropyridines; for example, utilizing the Knoevenagel modification, various substituted 1,5-dicarbonyl compounds can be prepared.

Making use of the Hantzsch dihydropyridine synthesis, M. Baley reported the first synthesis of an unsymmetrical 2, 2-6’2”-terpyridine.

This reaction has many applications. Commercially, 1,4-dihydropyridines are an important class of calcium channel blockers that help reduce blood pressure in patients with hypertension, e.g., nifedipine.