Kröhnke pyridine synthesis
In his work at the University of Giessen, Kröhnke observed condensation of α-pyridinium methyl ketone salts 1 with α,β-unsaturated carbonyl compounds 2 via a Michael reaction when treated with ammonium acetate to give 2,4,6-trisubstituted pyridines in high yields under mild reaction conditions.
The starting materials for the Kröhnke synthesis are often trivial to prepare, lending to the convenience and broad scope of the method.
This allows for straightforward construction of complex polyaryl systems, an attractive method for library synthesis of drug targets containing functionalized pyridine moieties.
The method tolerates a broad array of aryl substitiuents on both the α-pyridinium methyl ketone fragment and the α, β-unsaturated carbonyl compounds and can thus be used to generate a wide catalog of poly-aryl systems.
[10] Due to its broad scope, the Kröhnke method has seen wide applicability to for the synthesis of bipyridines (16), terpyridines (17), quaterpyridines (18) and even up to septipyridines (19) as shown below.
[11] The Kröhnke method is featured in a solvent-free synthesis of triarylpyridines that proceeds via a homo-coupling of two diaryl substituted α, β-unsaturated carbonyl compounds.
[12] This strategy offers a facile means for preparation of pyridnyl aryl systems that are important fragments of many useful drug scaffolds.
In 1992, Robinson and co-workers developed a similar pyridine synthesis using enamino nitriles as one of the three-carbon fragments in place of an α-pyridinium methyl ketone.
[16] These combinatorial variations of the Kröhnke reaction provide an efficient synthetic strategy to poly arylpyridine scaffolds.
Reaction with a chiral cyclic α, β-unsaturated ketone derived from 2-(+)-carene yielded the desired N, S-type ligand 38.
The Kröhnke reaction has also enjoyed applicability to the synthesis of a number of biologically active compounds in addition to ones cataloged in combinatorial studies.
[19] Polypyridine complex 43 was treated with N-Bromosuccinimide in wet tetrahydrofuran followed by pyridine to generate the acylmethylpyridinium salt 44 which can then undergo the macrocyclization under standard conditions to yield the desired product 45.
