Hantzsch Dihydropyridine (Pyridine) Synthesis

This reaction allows the preparation of dihydropyridine derivatives by condensation of an aldehyde with two equivalents of a β-ketoester in the presence of ammonia. Subsequent oxidation (or dehydrogenation) gives pyridine-3,5-dicarboxylates, which may also be decarboxylated to yield the corresponding pyridines.

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Mechanism of the Hantzsch Dihydropyridine Synthesis

The reaction can be visualized as proceeding through a Knoevenagel Condensation product as a key intermediate:

A second key intermediate is an ester enamine, which is produced by condensation of the second equivalent of the β-ketoester with ammonia:

Further condensation between these two fragments gives the dihydropyridine derivative:

Recent Literature

Efficient Synthesis of Hantzsch Esters and Polyhydroquinoline Derivatives in Aqueous Micelles
A. Kumar, R. A. Maurya, Synlett, 2008, 883-885.

'In situ'; Generated 'HCl'; - An Efficient Catalyst for Solvent-Free Hantzsch Reaction at Room Temperature: Synthesis of New Dihydropyridine Glycoconjugates
G. V. M. Sharma, K. L. Reddy, P. S. Lakshmi, P. R. Krishna, Synthesis, 2006, 55-58.

One-Pot Synthesis of 1,4-Dihydropyridines via a Phenylboronic Acid Catalyzed Hantzsch Three-Component Reaction
A. Debache, R. Boulcina, A. Belfaitah, S. Rhouati, B. Carboni, Synlett, 2008, 509-512.

Multicomponent Domino Cyclization-Oxidative Aromatization on a Bifunctional Pd/C/K-10 Catalyst: An Environmentally Benign Approach toward the Synthesis of Pyridines
O. De Paolis, J. Baffoe, S. M. Landge, B. Török, Synthesis, 2008, 3423-3428.

Covalently Anchored Sulfonic Acid on Silica Gel as an Efficient and Reusable Heterogeneous Catalyst for the One-Pot Synthesis of Hantzsch 1,4-Dihydropyridines under Solvent-Free Conditions
R. Gupta, R. Gupta, S. Paul, A. Loupy, Synthesis, 2007, 2835-2838.

Aluminum Chloride Promoted Hantzsch Reaction of N-Tosylhydrazones
H. Wang, M. Tang, Synthesis, 2017, 49, 4893-4898.

Facile Yb(OTf)₃ promoted one-pot synthesis of polyhydroquinoline derivatives through Hantzsch reaction
L.-M. Wang, J. Sheng, L. Zhang, J.-W. Han, Z.-Y. Fan, H. Tian, C.-T. Qian, Tetrahedron, 2005, 61, 1539-1543.