Hantzsch dihydropyridine synthesis

What is Hantzsch dihydropyridine synthesis?

The Hantzsch dihydropyridine synthesis, also known as the Hantzsch condensation or Hantzsch reaction, was initially reported by Hantzsch in 1882. The reaction involves the condensation of an aldehyde with 2 equivalents of β-ketoester in the presence of ammonia to produce dihydropyridine dicarboxylate, which is commonly referred to as the Hantzsch ester. Upon subsequent oxidation or dehydrogenation, pyridine-3,5-dicarboxylates can be formed, which may be further decarboxylated to yield the corresponding pyridines.

Hantzsch dihydropyridine synthesis - general reaction scheme - Hantzsch condensation - Hantzsch reaction
Hantzsch dihydropyridine synthesis

The Hantzsch ester, which acts as a calcium antagonist, is widely used in drug design and can also serve as a source of hydrogen. Microwave irradiation has been used to modify the reaction, resulting in high reaction rates and yields.

Other modifications to the Hantzsch dihydropyridine synthesis include the use of alkylidene or arylidene 1,3-dicarbonyl compounds to form unsymmetrical 1,4-dihydropyridines and the condensation of aminocrotonic ester with aldehyde under acidic conditions to produce 3,5-dicyanodihydropyridines.

It is worth noting that the specific synthesis of 2,4,6-trimethylpyridine, also known as collidine, is referred to as the Hantzsch collidine synthesis.