Kröhnke pyridine synthesis

The Kröhnke pyridine synthesis is reaction in organic synthesis between α-pyridinium methyl ketone salts and α, β-unsaturated carbonyl compounds used to generate highly functionalized pyridines. Pyridines occur widely in natural and synthetic products, so there is wide interest in routes for their synthesis. The method is named after Dr. Fritz Kröhnke. The Kröhnke pyridine synthesis is reaction in organic synthesis between α-pyridinium methyl ketone salts and α, β-unsaturated carbonyl compounds used to generate highly functionalized pyridines. Pyridines occur widely in natural and synthetic products, so there is wide interest in routes for their synthesis. The method is named after Dr. Fritz Kröhnke. 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 proposed intermediates, 1, 5-dicarbonyl compound 3, have not been isolated. Since its discovery, the Kröhnke synthesis has enjoyed broad applicability to the preparation of di-,tri- and tetrapyridine derivatives, demonstrating a number of advantages over related reactions such as the Hantzsch pyridine synthesis. The mechanism of the Kröhnke pyridine synthesis begins with enolization of α-pyridinium methyl ketone 4 followed by 1,4-addition to the α, β-unsaturated ketone 5 to form the Michael adduct 6, which immediately tautomerizes to the 1,5-dicarbonyl 7. Addition of ammonia to 7 followed by dehydration via 8 generates the imine intermediate 9., The imine intermediate is then deprotonated to enamine 10 and cyclizes with the carbonyl to generate intermediate 11. The pyridinium cation is then eliminated to form hydroxy-dienamine 12. Aromatization of 12 via subsequent loss of water generates the desired pyridine heterocycle 13. The starting materials for the Kröhnke synthesis are often trivial to prepare, lending to the convenience and broad scope of the method. Preparation of the α-pyridinium methyl ketone salts can be easily achieved by treatment of the corresponding α-bromo methyl ketone with pyridine. The α,β-unsaturated ketones are often available commercially or can be prepared using a number of known methods. Additionally, Mannich bases can also be utilized as the Michael acceptor for the scheme, further diversifying the scope of starting materials that can be incorporated into the Kröhnke scheme. The reaction conditions for the Kröhnke synthesis are generally facile and the reactions often proceed in high yields with reaction temperatures generally not exceeding 140 °C. The Kröhnke synthesis is generally performed in either glacial acetic acid or methanol, but it can also be done under aqueous conditions, and more recently under solvent-free conditions. 1,3-dicarbonyl compounds have also been shown to be viable starting materials in place of the α-pyridinium methyl ketone salts. For example, treatment of 1,3-diketone 14 with base in ethanol followed by ammonium acetate, acetic acid, the corresponding enone and a Lewis acid yields 3-acyltriarylpyridines of the form 15. These acyl pyridine are attractive intermediates because they have an electrophilic handle that allows for additional functionality to be incorporated into the molecule. This allows for straightforward construction of complex polyaryl systems, an attractive method for library synthesis of drug targets containing functionalized pyridine moieties. The Kröhnke synthesis for making pyridines possesses a number of succinct advantages over other methods. Unlike the Hantzsch synthesis, the Kröhnke method does not require oxidation to generate the desired product since the α-pyridinium methyl ketone already possesses the correct oxidation state. Another advantage of the Kröhnke synthesis is its high atom economy. For example, the Chichibabin synthesis requires 2 equivalents of unsaturated starting material. Additionally, the byproducts of the Kröhnke synthesis is water and pyridine, which allow for easy workup and purification protocols. Unlike comparable methods for pyridine synthesis, the Kröhkne synthesis benefits from being a high-yielding one pot synthesis, which ultimately allows for abbreviation of synthetic pathways and further simplifies combinatorial library cataloging. The broad scope of the Kröhnke pyridine synthesis has made it particularly useful for the synthesis of poly aryl systems including pyridyl, thienyl, and furanyl moieties as well. 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. Additionally, electron-withdrawing groups and electron-donating groups on the incoming aryl substituents are both well tolerated. The Kröhnke synthesis can also employ alkyl and vinyl substituents giving moderated to good yields as well. 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.