1. Hantzsch Synthesis: A three-component reaction between an aldehyde, a β-ketoester or β-diketone, and ammonia.
The Hantzsch pyridine synthesis or Hantzsch dihydropyridine synthesis is a multi-component organic reaction between an aldehyde such as formaldehyde, 2 equivalents of a β-keto ester such as ethyl acetoacetate and a nitrogen donor such as ammonium acetate or ammonia.[1][2] The initial reaction product is a dihydropyridine which can be oxidized in a subsequent step to a pyridine.[3] The driving force for this second reaction step is aromatization. This reaction was reported in 1881 by Arthur Rudolf Hantzsch.
2. Chichibabin Synthesis: A reaction between an aldehyde or ketone and ammonia or a primary amine in the presence of a strong base.
The syntheses are presently conduced commercially in the presence of oxide catalysts such as modified alumina (Al2O3) or silica]] (SiO2). The reactants are passed over the catalyst at 350-500 °C. 2-Methylpyridine- and 4-methylpyridine are produced as a mixture from acetaldehyde and ammonia. 3-Methylpyridine and pyridine are produced from acrolein and ammonia. Acrolein and propionaldehyde react with ammonia affords mainly 3-methylpyridine. 5-Ethyl-2-methylpyridine is produced from paraldehyde and ammonia.
3. Bönnemann Cyclization: A palladium-catalyzed cyclization of an alkyne with a nitrile in the presence of a reducing agent such as zinc.
4. Skraup Synthesis: A Six-membered heterocyclic ring is formed by condensing aniline with a ketone or aldehyde and sulfuric acid as a catalyst.
5. Bohlmann-Rahtz Pyridine Synthesis: An oxidative coupling reaction between an alkyne and a nitrile or α,β-unsaturated carbonyl compound in the presence of a Lewis acid such as copper acetate.
The Bohlmann-Rahtz Pyridine Synthesis allows the generation of substituted pyridines in two steps. Condensation of enamines with ethynylketones leads to an aminodiene intermediate that, after heat-induced E/Z isomerization, undergoes a cyclodehydration to yield 2,3,6-trisubstituted pyridines.
High cyclodehydration temperatures are therefore required to facilitate Z/E isomerizations that are a prerequisite for heteroannelation.
These methods can produce substituted and unsubstituted pyridines with varying yields and selectivities depending on the specific reaction conditions and substrates used.
Comments