Hantzsch dihydropyridine synthesis – a heterocycle formation reaction

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.

Review available Thermo Scientific products for the Hantzsch dihydropyridine synthesis: